Key features of human DC subsets.
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"7396",leadTitle:null,fullTitle:"Panorama of Contemporary Quantum Mechanics - Concepts and Applications",title:"Panorama of Contemporary Quantum Mechanics",subtitle:"Concepts and Applications",reviewType:"peer-reviewed",abstract:"This book is devoted to recent developments in quantum mechanics. After an Introductory chapter, Chapter 2 describes the cooperative spontaneous lasing mechanism in gas in three level systems and their possible quantum retardation effects. Chapter 3 is concerned with the evolution of states of large quantum particle systems via marginal correlation operators. Chapter 4 studies the effects of electronic transfer using ab initio quantum calculation methods to access biological macromolecular system behaviors. Chapter 5 concentrates on new features of supersymmetric quantum mechanics using the adjunction of boson-fermion symmetry. The book will be of interest to graduate and Ph.D students as well as scientists from various backgrounds who are concerned with quantum effects.",isbn:"978-1-83962-666-1",printIsbn:"978-1-83962-665-4",pdfIsbn:"978-1-83962-667-8",doi:"10.5772/intechopen.75282",price:119,priceEur:129,priceUsd:155,slug:"panorama-of-contemporary-quantum-mechanics-concepts-and-applications",numberOfPages:108,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"e78f2cfea2dec9fab1f269c994faa0d4",bookSignature:"Tuong T. Truong",publishedDate:"December 4th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7396.jpg",numberOfDownloads:3258,numberOfWosCitations:2,numberOfCrossrefCitations:0,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:1,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:3,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 12th 2018",dateEndSecondStepPublish:"August 2nd 2018",dateEndThirdStepPublish:"October 1st 2018",dateEndFourthStepPublish:"December 20th 2018",dateEndFifthStepPublish:"February 18th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"143434",title:"Prof.",name:"Trong Tuong",middleName:null,surname:"Truong",slug:"trong-tuong-truong",fullName:"Trong Tuong Truong",profilePictureURL:"https://mts.intechopen.com/storage/users/143434/images/system/143434.png",biography:"T. T. Truong holds a Ph.D in theoretical physics from Columbia University in New York, N.Y., USA in 1973 and a Habilitation degree from Free University in Berlin Germany in 1987. He has been professor of physics at the university of Tours, France before moving to the university of Cergy-Pontoise, France, where he is now emeritus professor of physics. His main interests are in Quantum Mechanics, Integrable Systems in statistical physics and quantum field theory in low dimensions, super-integrable quantum mechanics, quantum dots and integral geometry for imaging science.",institutionString:"University of Cergy-Pontoise",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Cergy-Pontoise University",institutionURL:null,country:{name:"France"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"230",title:"Quantum Mechanics",slug:"quantum-mechanics"}],chapters:[{id:"65303",title:"Canceled: Topological Insulating States in Atom-Thin Layers",doi:"10.5772/intechopen.82848",slug:"topological-insulating-states-in-atom-thin-layers",totalDownloads:585,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The introduction of spin-orbit interactions (SOIs) and the subsequent realization of two-dimensional (2D) topological insulating (TI) states are crucial for innovative spintronic devices with low-power dissipation and quantum devices. However, the 2D TI states have been mainly researched in semiconductor quantum well systems. Graphene basically lacks SOIs due to the low mass of the carbon atom, and none reported its TI states. In this chapter, I describe the introduction of SOIs into graphene by random decoration of heavy nanoparticles (B2Te3 or Pt) with low coverage ratios using an original nanoneedle method. The decoration with less damages and contaminations leads to the emergence of particle density-dependent nonlocal resistance (RNL) peaks at room temperature and those oscillatory behaviors under in-plane magnetic fields, which suggest presence of the SOI gaps. Moreover, 2D TI states are confirmed when the same method is applied to six or four terminal small patterns of graphene with coverage as small as 3%. The present observation opens the door to realizing the 2D TI phases of graphene and paves a way for their application to innovative spintronic and quantum devices.",signatures:"Junji Haruyama",downloadPdfUrl:"/chapter/pdf-download/65303",previewPdfUrl:"/chapter/pdf-preview/65303",authors:[null],corrections:null},{id:"67030",title:"Cooperative Spontaneous Lasing and Possible Quantum Retardation Effects",doi:"10.5772/intechopen.83013",slug:"cooperative-spontaneous-lasing-and-possible-quantum-retardation-effects",totalDownloads:719,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The collective decay effects between the dipole-active three-level subsystems in the nonlinear interaction with dipole-forbidden transitions, like \n\n2\nS\n−\n1\nS\n\n of hydrogen-like radiators, are proposed, taking into consideration the cooperative exchanges between two species of atoms through the vacuum field in the scattering and the two-photon resonance processes. One of them corresponds to the situation when the total energy of the emitted two photons by the three-level radiator in the cascade configuration enters into the two-photon resonance with another type of dipole-forbidden transitions of hydrogen-like (or helium-like) atoms. The similar situation appears in the cooperative scattering between two species of quantum emitters when the difference of the excited energies of the two dipole-active transitions of the three-level radiators is in the resonance with the dipole-forbidden transitions of the Hydrogen-like radiators. These effects are accompanied by the interference between single- and two-quantum collective transitions of the inverted radiators from the ensemble. The two-particle collective decay rate is defined in the description of the atomic correlation functions taking into consideration the phase retardation between them. The kinetic equations which describe the cooperative processes as the function of time and correlation are obtained. The behavior of the system of radiators at short and long time intervals in comparison with the retardation time between them is studied.",signatures:"Nicolae A. Enaki",downloadPdfUrl:"/chapter/pdf-download/67030",previewPdfUrl:"/chapter/pdf-preview/67030",authors:[{id:"249993",title:"Dr.",name:"Nicolae",surname:"Enaki",slug:"nicolae-enaki",fullName:"Nicolae Enaki"}],corrections:null},{id:"65011",title:"Processes of Creation and Propagation of Correlations in Large Quantum Particle System",doi:"10.5772/intechopen.82836",slug:"processes-of-creation-and-propagation-of-correlations-in-large-quantum-particle-system",totalDownloads:588,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"We review new approaches to the description of the evolution of states of large quantum particle systems by means of the marginal correlation operators. Using the definition of marginal correlation operators within the framework of dynamics of correlations governed by the von Neumann hierarchy, we establish that a sequence of such operators is governed by the nonlinear quantum BBGKY hierarchy. The constructed nonperturbative solution of the Cauchy problem to this hierarchy of nonlinear evolution equations describes the processes of the creation and the propagation of correlations in large quantum particle systems. Furthermore, we consider the problem of the rigorous description of collective behavior of quantum many-particle systems by means of a one-particle (marginal) correlation operator that is a solution of the generalized quantum kinetic equation with initial correlations, in particular, correlations characterizing the condensed states of systems.",signatures:"Viktor I. Gerasimenko",downloadPdfUrl:"/chapter/pdf-download/65011",previewPdfUrl:"/chapter/pdf-preview/65011",authors:[{id:"211077",title:"Prof.",name:"Viktor",surname:"Gerasimenko",slug:"viktor-gerasimenko",fullName:"Viktor Gerasimenko"}],corrections:null},{id:"65493",title:"Recent Progresses in Ab Initio Electronic Structure Calculation toward Understandings of Functional Mechanisms of Biological Macromolecular Systems",doi:"10.5772/intechopen.83545",slug:"recent-progresses-in-em-ab-initio-em-electronic-structure-calculation-toward-understandings-of-funct",totalDownloads:622,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In this chapter, we present recent advances of theoretical analyses toward understandings of functional mechanisms of biological macromolecular systems, employing ab initio electronic structure calculations. Two distinct types of triggers to invoke dramatic rearrangements of electronic structures in the reaction centers are revealed by full ab initio quantum mechanics (QM) calculations (first example) and hybrid ab initio QM/molecular mechanics (MM) molecular dynamics (MD) calculations (second example). First, we demonstrate dramatic rearrangements of molecular orbitals (MOs) induced by binding of a hydroxyl ion (OH−) to the [4Fe-3S] cluster found in hydrogenases, which catalyzes both dissociation and production of dihydrogen (H2). This induces the significant delocalization of the LUMO, resulting in formation of electron transfer pathways required for the catalysis. Thus, in organisms, just a tiny species (e.g. OH− ligand) can play a key role for the biological functions. Second, we indicate dynamical rearrangements of MOs occurring in the enzymatic reactions of RNA-protein complexes. As the catalysis proceeds, the reactive MOs, which do not belong to the frontier orbitals in the initial stages of the reaction, are dramatically reconstituted in the hybrid ab initio QM/MM MD simulations, resulting in the frontier orbitals, which is a feature characteristic to biological macromolecular systems.",signatures:"Jiyoung Kang, Takuya Sumi and Masaru Tateno",downloadPdfUrl:"/chapter/pdf-download/65493",previewPdfUrl:"/chapter/pdf-preview/65493",authors:[null],corrections:null},{id:"66182",title:"Supersymmetric Quantum Mechanics: Two Factorization Schemes and Quasi-Exactly Solvable Potentials",doi:"10.5772/intechopen.82254",slug:"supersymmetric-quantum-mechanics-two-factorization-schemes-and-quasi-exactly-solvable-potentials",totalDownloads:747,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"We present the general ideas on supersymmetric quantum mechanics (SUSY-QM) using different representations for the operators in question, which are defined by the corresponding bosonic Hamiltonian as part of SUSY Hamiltonian and its supercharges, which are defined as matrix or differential operators. We show that, although most of the SUSY partners of one-dimensional Schrödinger problems have already been found, there are still some unveiled aspects of the factorization procedure which may lead to richer insights of the problem involved.",signatures:"José Socorro García Díaz, Marco A. 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Neimyer, Kailey Roberts,\nWendy Lichtenthal, Jun Hu and Matthias Rauterberg",dateSubmitted:"September 5th 2017",dateReviewed:null,datePrePublished:null,datePublished:"October 18th 2017",book:{id:"6456",title:"Proceedings of the Conference on Design and Semantics of Form and Movement",subtitle:"Sense and Sensitivity, DeSForM 2017",fullTitle:"Proceedings of the Conference on Design and Semantics of Form and Movement - Sense and Sensitivity, DeSForM 2017",slug:"proceedings-of-the-conference-on-design-and-semantics-of-form-and-movement-sense-and-sensitivity-desform-2017",publishedDate:"October 18th 2017",bookSignature:"Miguel Bruns Alonso and Elif Ozcan",coverURL:"https://cdn.intechopen.com/books/images_new/6456.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"156855",title:"Dr.",name:"Elif",middleName:null,surname:"Ozcan",slug:"elif-ozcan",fullName:"Elif Ozcan"}],productType:{id:"2",title:"Proceeding",chapterContentType:"conference paper",authoredCaption:"Edited by"}},authors:[{id:"221149",title:"Dr.",name:"Wan Jou",middleName:null,surname:"She",fullName:"Wan Jou She",slug:"wan-jou-she",email:"lave@lavendershe.com",position:null,institution:null}]},book:{id:"6456",title:"Proceedings of the Conference on Design and Semantics of Form and Movement",subtitle:"Sense and Sensitivity, DeSForM 2017",fullTitle:"Proceedings of the Conference on Design and Semantics of Form and Movement - Sense and Sensitivity, DeSForM 2017",slug:"proceedings-of-the-conference-on-design-and-semantics-of-form-and-movement-sense-and-sensitivity-desform-2017",publishedDate:"October 18th 2017",bookSignature:"Miguel Bruns Alonso and Elif Ozcan",coverURL:"https://cdn.intechopen.com/books/images_new/6456.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"156855",title:"Dr.",name:"Elif",middleName:null,surname:"Ozcan",slug:"elif-ozcan",fullName:"Elif Ozcan"}],productType:{id:"2",title:"Proceeding",chapterContentType:"conference paper",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11890",leadTitle:null,title:"Cognitive Behavioral Therapy - Basic Principles and Application Areas",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tThoughts, emotions, behaviors, and body sensations are interrelated, and a change in one of these structures can affect the others. Today, cognitive-behavioral therapy (CBT) is in the position of a psychotherapy school with a wide application area, which includes a group psychotherapy approach based on this view. CBT is an effective treatment approach for many mental disorders/problems such as depression, anxiety disorders, alcohol-substance use disorders, marital problems, eating disorders, and severe mental disorders. Numerous studies have demonstrated the positive effect of CBT on functionality and quality of life. Since its emergence, CBT has made significant advances in clinical practice and research. This book will cover the historical development, basic principles, and application areas of CBT. It is aimed that the book chapters are prepared in the light of current literature findings will be an essential reference source for the readers.
",isbn:"978-1-83969-897-2",printIsbn:"978-1-83969-896-5",pdfIsbn:"978-1-83969-898-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"849acf69df0db62876816078930b4481",bookSignature:"Prof. Cicek Hocaoglu",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11890.jpg",keywords:"Exposure, Homework Assignments, Formulation, Treatment Rationale, Depression, Anxiety Disorders, Eating Disorders, Personality Disorders, Obsessive Compulsive Disorder, Cognitive Behavioral Therapy, Psychotherapy, Dysthymia",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 3rd 2022",dateEndSecondStepPublish:"July 6th 2022",dateEndThirdStepPublish:"September 4th 2022",dateEndFourthStepPublish:"November 23rd 2022",dateEndFifthStepPublish:"January 22nd 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Cicek Hocaoglu received postgraduate training in psychiatry at the Medical School of Karadeniz Technical University. She is currently a Professor and Head of the Department of Psychiatry at the Recep Tayyip Erdogan University Medical School. She has published over 100 national/international scientific articles, book chapters, and papers presented. Her interests include consultation-liaison psychiatry, suicide, schizophrenia, anxiety disorders, bipolar disorder, and psychopharmacology.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"28322",title:"Prof.",name:"Cicek",middleName:null,surname:"Hocaoglu",slug:"cicek-hocaoglu",fullName:"Cicek Hocaoglu",profilePictureURL:"https://mts.intechopen.com/storage/users/28322/images/system/28322.jpg",biography:"Cicek Hocaoglu obtained her medical degree from Uludag University Faculty of Medicine, Bursa, Turkey. She received postgraduate training in psychiatry at the Medical School of Karadeniz Technical University, Trabzon, Turkey. She is currently Professor and Head of the Department of Psychiatry at the Recep Tayyip Erdogan University Medical School, Rize, Turkey. She has many published national/international scientific articles, book chapters, and papers presented in congresses. Her interests include consultation-liaison psychiatry, suicide, schizophrenia, anxiety disorders, bipolar disorder, and psychopharmacology.",institutionString:"Recep Tayyip Erdoğan University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Recep Tayyip Erdoğan University",institutionURL:null,country:{name:"Turkey"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"466997",firstName:"Patricia",lastName:"Kerep",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/466997/images/21565_n.jpg",email:"patricia@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully"}},relatedBooks:[{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. Mauricio Barría",coverURL:"https://cdn.intechopen.com/books/images_new/6550.jpg",editedByType:"Edited by",editors:[{id:"88861",title:"Dr.",name:"R. Mauricio",surname:"Barría",slug:"r.-mauricio-barria",fullName:"R. 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They are a rare, heterogeneous population of haematopoietic cells that are equipped to capture, process and present antigen (Ag) to the adaptive immune system.
In a non-inflamed or steady state setting, DCs constantly sample the local environment for Ags and have the potential to induce peripheral tolerance via T cell anergy or deletion [1]. DCs recognise danger via pattern recognition receptors (PRR) on their cell surface, the cytoplasm and within cellular organelles [2]. Ligation of PRRs by pathogen associated molecular patterns (PAMPs) or damage associated molecular patterns (DAMPs), activates DC and licences DC to upregulate co-stimulatory marker expression such as CD86 and CD80 on their cell surface and initiate immunogenic T cell priming.
DCs situated in non-lymphoid tissues, also known as migratory DCs, constantly migrate to draining lymph nodes (LNs), maturing during this process, to present Ag to naïve T cells. Resident DCs in lymphoid organs are immature and maintain tolerance during steady state, but can stimulate naïve T cells when activated
In humans, the majority of DC characterisation studies are of DCs isolated from the blood due to the rarity of the cell type and limited access to human tissue samples, although more investigations on non-lymphoid DCs in the skin, lung and liver have recently emerged [4, 5, 6, 7]. DCs in the blood comprise ~1% of total peripheral blood mononuclear cells (PBMCs) and are traditionally identified by the high expression of MHCII (HLA-DR) and the lack of lineage markers CD3, CD14, CD15, CD19, CD20 and CD56, although the latter marker has recently been shown to be expressed on gut and other non-lymphoid DCs [6].
Human blood DCs can be divided into conventional DCs (cDCs) and plasmacytoid DCs (pDCs), which are HLA-DRhiCD11c+123− and HLA-DRhiCD11c−123+ respectively. Human blood cDCs are further categorised into cDC1 and cDC2 subsets. Additionally, there are monocyte-derived DCs that originate separately from cDCs and pDC precursors. The recent use of whole population and single cell sequencing techniques has been instrumental in elucidating transcription factors and surface markers that are unique to each DC subset, which has helped identify relationships between DC subsets across species and tissues as well as corroborate DC functional analyses [6, 7, 8, 9], summarised in Table 1.
DC subsets | |||
---|---|---|---|
cDC1 | cDC2 | pDC | |
Surface phenotype | CD11c+HLA-DR+ CD123−CLEC9A+ XCR1+Necl2+ CD141+ CD11b−CD172α− | CD11c+HLA-DR+CD123− CD1c+CD11b+CD172α+ CLEC10A+ with further subdivision based on CD5hiCD32B+CD163−CD36− or CD5loCD32B−CD163+CD36+ | CD11c−HLA-DR+ CD123+CD303+ CD304+CD45RA+ CD2+/− |
Transcription factors | |||
PRR expression | TLR3, 8 | TLR2, cytosolic RNA sensors (RIG-I, MDA-5), STING | TLR7, 9, STING |
Ag presentation | Cross-presentation of cellular Ag | Cross-presentation of soluble Ag | CD4+ and CD8+ T cell priming* |
Roles in immunity | Potent producer of Type III IFN (after TLR3 stimulation), CTL priming, Th1 response | Th1, Th17 response | Potent producers of Type I and III IFN and mediating anti-viral immunity |
Key features of human DC subsets.
Previous Ag presentation abilities by pDCs are now suggested to be contributed by contaminating AXL+Siglec6+ (AS) DCs.
cDC1s constitute ~0.03% of PBMCs and are found in the blood, tonsil, spleen and non-lymphoid tissues such as the skin. They were classically defined by the high expression of CD141 (blood DC antigen 3 (BDCA3) or thrombomodulin) [10]. However, CD141 is not a completely specific marker for cDC1 as it is also expressed on endothelial cells, monocytes and other DC subsets [8]. Using phenotypic, transcriptional and functional assays, these CD141+ DCs have been further characterised as CD11c+HLA-DR+CD11b−CD172a− CLEC9a+XCR1+Necl2+ cells that lack monocytic markers CD14 and CD16 [4, 11] identifying them as human cDC1 [12, 13, 14, 15, 16].
The dependence of CD141+ DCs on Flt3 ligand (FL), an important DC developmental factor, has been demonstrated
PRRs expressed by human cDC1s are predominantly Toll-like receptor (TLR) 3, located in endosomes and which recognises double-stranded RNA and TLR8, also located in endosomes and which recognises bacterial ssRNA and mammalian mitochondrial RNA [10, 22]. In response to TLR3 signals [23] and also HCV
The cDC1s are superior to other DC subsets in their ability to present ex
Human cDC2, traditionally known as CD1c+ or BDCA1+ DCs, constitute ~1% of PBMCs and can be identified by the expression of CD11c, CD11b, CD13, CD33, CD172a, HLA-DR and CD45RO [2, 10, 26]. The phenotypic similarities between these DCs and moDCs, as well as the expression of CD1c on B cells and other DC subsets, have made the precise segregation of this subset quite difficult. Although previous studies have used CD64 to exclude monocytes from bonafide CD1c+ DCs in the blood, cDCs express low levels of this marker and cannot be definitively used to separate the cell populations [6, 7]. More recently, the use of single cell RNA sequencing techniques has identified additional surface phenotypic markers, such as
The cDC2 DCs highly express TLR2 and also express a range of cytosolic viral RNA sensors such as RIG-I [30, 31]. Different proposed cDC2 subsets also seem to have different PRR expression patterns. For example, CD5hi cDC2 express high levels of TLR7 and 8 compared to CD5lo cDC2 and CD32B+ cDC2 express higher levels of
Activated cDC2s can drive Th17 immune response and can also produce high levels of IL-12p70, potentially inducing Th1 differentiation [2, 29]. However, current data suggests Th17 versus Th1 driven responses may be independently driven by CD5+ versus CD5lo cDC2 subsets, respectively [8, 28].
Human cDC2s are able to cross-present
The pDCs constitute ~0.01–0.04% of PBMCs and commonly reside in secondary lymphoid organs localising in the follicular cortex, T cell nodules and around high endothelial venules [36, 37]. As their name suggests, pDCs are similar in morphology to that of plasma cells. Under light microscopy, pDCs are observed to be spherical in shape with a rounded nucleus, often predominant endoplasmic reticulum and present as clusters in T-cell rich regions of lymphoid tissue [36, 37, 38].
The pDCs, originally identified as ‘natural interferon producing cells’ (NIPC), are renowned for their ability to drive immense type I and type III IFN production via TLRs 7 and 9 [39, 40, 41]. This IFN production is essential to combat viral infection but pDC-derived IFN is also thought to contribute to disease in autoimmune diseases including systemic lupus erythematosus [42]. They are also thought to play a role in Th2 induction and asthma progression in humans [42]. Conversely, pDC have also been shown to play a major role in tolerance
pDCs are recognised as being CD11c−/loCD45RA+CD123+CD303+CD304+HLA-DR+ and can express CD56 (reviewed in [2]). pDCs may also be identified by their transcription factors including; TCF4 (also known as E2-2), SPIB, ZEB2, IRF8, IRF7 and IRF4 [43, 44, 45]. Haploinsufficiency in the
The pDCs can be divided into 2 subsets based on CD2 expression [47]. Recent single cell transcriptomic profiling of blood DCs from healthy donors has revealed that CD2+ ‘pDC’ also express AXL and SIGLEC6 (known as AS DCs). These AS DCs can stimulate CD4+ and CD8+ allogeneic T cell proliferation whereas the segregation of pDCs away from contaminating AS DCs demonstrated potent IFN-α production after TLR9 stimulation and a lack of T cell priming attributes [8]. Whether AS DCs and pDC are 2 distinct cell types or differentiation stages of one another is yet to be defined.
A rare and highly aggressive acute leukaemia known as Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) involves the malignancy of pDC precursors [48], driven, at least in part by the juxtaposition of the pDC-specific RUNX2 enhancer and the MYC promotor due to the chromosomal translocation (6;8)(p21;q24) [49]. The BPDCN can be reliably identified by immunohistochemical staining with TCF4 and CD123 antibodies [50]. BPDCNs most commonly present as skin lesions and may be accompanied by swelling of other organs such as the lymph nodes, bone marrow or spleen. Standard chemotherapy treatments for myeloid neoplasms often result in poor prognosis [51] although a toxin-conjugated anti-CD123 drug, tagraxofusp-erzs, has recently been approved as the first FDA-approved BPDCN-specific treatment [52].
Monocyte derived DC (moDC) refers to DCs induced from monocytes with GM-CSF
It still remains unclear whether the moDC actually represent an
While the
The ability to present Ag and activate the adaptive immune response makes DCs an attractive target to re-invigorate anti-cancer immunity. There are different types of DC vaccines, with the most common type involving the
Thus far, a wide variety of moDC vaccine strategies have been trialled [68]. moDCs have been differentiated and matured using monocyte conditioned medium with various supplements of cytokines (TNF-α, GM-CSF, IL-4, IFN-α), TLR agonists (LPS) and other factors such as prostaglandin E2 [67, 68, 69]. There is also variety in the type of Ags loaded into DCs such as peptides from tumour-associated Ags (TAA), TAA-encoding mRNA and whole tumour lysates [67]. More recently, the electroporation of synthetic mRNA encoding DC-maturation factors such as CD40 ligand, constitutively active TLR4 and CD70 together with fusion proteins DC-LAMP and melanoma-associated Ags into autologous moDCs (TriMixDC-MEL) have proven safe and immunogenic in phase 1 clinical trials in metastatic melanoma [70]. However, the variation in the aforementioned vaccine factors as well as the route of DC administration (intranodal, i.v.) and lack of standardised method of moDC generation has shown variable efficacies of moDC vaccines in clinical outcomes.
More recent clinical trials using naturally circulating blood DCs have turned to CliniMACS system by Miltenyi to isolate different DC subsets from patients (Figure 1). Two completed Phase I clinical trials have used CD1c+ DCs (cDC2) loaded with TAA peptides in hormone refractory metastatic prostate cancer and metastatic melanoma and observed good safety and immunogenicity [71, 72]. Another completed Phase I trial using pDCs showed the induction of tumour-Ag specific CTL response as well as an IFN signature [33]. On-going clinical trials, as summarised by Bol et al., are not only isolating single DC subsets for vaccination, but are also trying combination vaccines comprised of cDC2 and pDC subsets and using dual-activating maturation agonists such as single stranded RNA that stimulates TLR8 on cDC2 and TLR7 on pDCs (NCT-02993315, NCT-02574377, NCT-02692976) [67]. However, there are still many challenges in using naturally circulating blood DCs in tumour vaccinations. The methodology for isolation of sufficient CD141+ cDC1 DCs, which comprise only 0.03% PBMCs, is still lacking and will be important to harness due to their superior ability to cross-present dead and necrotic Ag. Furthermore, although improved over the years, the duration of DCs spent
Overview of potential roles of DC in cancer therapies. To improve current cancer treatments and the activation of tumour-specific CTL, DC may be directly targeted
Apart from the
The tumour microenvironment (TME) is a complex niche of tumour cells, stromal cells and tumour infiltrating myeloid and lymphoid immune cells. The dynamic nature of this niche varies with different types and stages of cancer, as well as between patients themselves. It has been established that the infiltration of CD8+ cytotoxic T cells have been associated with better treatment outcomes with checkpoint blockade therapies in a number of cancer types including metastatic melanoma [83]. However, the phenotype and role of tumour-infiltrating DCs (TIDCs) are less clear, possibly due to the lack of consistent markers probing DCs within the TME and the lack of distinctions between monocyte and putative DC subsets [84].
Using immunohistochemistry staining, many studies have previously used CD1a and S100 proteins to identify TIDCs. The higher density of these cells within tumours correlated with better clinical outcomes in melanoma and head and neck cancers [84, 85]. However, discrepancies in this correlation were reported in colon, breast, gastric, nasopharyngeal, lung and ovarian cancers [84, 86, 87, 88]. One major factor that could explain these reported discrepancies is the markers used to identify DCs. CD1a and S100 are expressed at different levels on Langerhans cells (LCs), interdigitating DCs and moDCs, but not on cDCs or pDCs and the expression of these markers on epithelial-tropic DCs such as LCs could account for the strong correlations observed in only the epithelial cancers [84]. Furthermore, DC activation markers CD83 and DC-LAMP were used to identify mature DCs, though CD83 is not expressed in all DC subsets [7, 84, 89]. In breast adenocarcinoma patients, immature DCs were found to localise within the tumour whereas CD83/DC-LAMP+ mature DCs localised in the peri-tumour edges [90]. Some studies have reported significant correlations between the intratumoral infiltration of mature DCs with better clinical outcomes. For example, a recent report showed that the recruitment of DC-LAMPhi cells into the tumour stroma exhibited strong correlations with significantly higher overall and relapse-free survival in high-grade serous ovarian carcinoma [91]. However, this correlation has also been inconsistent in a number of different cancers [85, 90, 92, 93, 94].
More recently, with the establishment of The Cancer Genome Atlas (TCGA) program, scientists are able to compare DC-specific signatures with a publicly available molecular and clinical database of a vast array of cancers. In melanoma and breast cancer patients, DC-specific genes such as
Whilst the recent data above points towards a benefit of the infiltration of conventional DC into tumour sites, the correlation between tumour infiltrating pDCs and poor survival prognosis is clear. This has been described in breast, head and neck, ovarian and lung cancers [100, 101, 102, 103] where it is thought that pDC-induced tolerance and impaired IFN-α production contributes to a suppressive, non-immunogenic TME. Indeed mouse studies point to a role of TGF-β in the tumour environment in preventing an activatory phenotype of pDC and favouring a tolerising, IDO producing phenotype [104].
Further factors within the TME that have been illustrated to correlate with DC infiltration or function include for example, vascular endothelial growth factor (VEGF), a tumour angiogenic factor, inversely correlated with DC density and overall survival in gastric adenocarcinoma tissues [87, 105]. High serum VEGF levels were also associated with low blood cDC1 and cDC2 numbers in colorectal and non-small cell lung cancers and treatment of VEGF decoy receptor, VEGF-Trap, increased the proportion of mature DCs, but not overall numbers or DC priming function in various solid cancer patients [106, 107, 108]. Direct evidence of VEGF-induced DC inhibition was also reported in DCs differentiated from CD34+ precursors and moDCs [105, 106, 109]. Other cytokines such as IL-6, IL-10 and TGFβ have also demonstrated DC-inhibitory effects in the TME [104, 110, 111, 112, 113, 114].
In metastatic melanoma patients, higher active β-catenin signalling within the tumour was associated with low cDC1 signatures and T cell signatures [115]. Furthermore, the expression of fatty acid synthase was inversely correlated with CD11c+ DC signatures in ovarian, prostate and bladder cancers [116].
Chemotherapy and radiotherapy have remained the core pillars of cancer treatments. However, the combination of these traditional therapies with immunotherapies targeting immune checkpoint receptors has greatly enhanced patient clinical outcomes, especially in patients with immunogenic cancers, summarised in Table 2.
Checkpoint inhibitor (CI) | CI cell expression | Ligand | Ligand cell expression | Anti-CI mAb clinical name | Clinical outcome |
---|---|---|---|---|---|
PD-1 | T, B, NK cells, DC | PD-L1/2 | PD-L1: DC, monocytes, Treg, cells, tumour; PD-L2: Activated cDC, moDCs | Pembrolizumab, Nivolumab | Approved for metastatic melanoma, renal cell carcinoma, squamous-cell carcinoma of head and neck, Hodgkin’s lymphoma, metastatic colorectal, non-small cell lung, Merkel cell and ovarian cancers Improved clinical outcomes in combination with peptide/vector vaccines for advanced solid cancers, metastatic melanoma and HPV-16-related cancers |
CTLA4 | T cells, activated moDCs | CD80/86 (B7.1/2) | APC | Ipilimumab, Tremelimumab | Approved for metastatic melanoma, renal cell carcinoma and colorectal cancer treatments Mixed results in combination with peptide and moDC vaccines |
TIM-3 | T, B cells, cDC, myeloid cells | Galectin-9, CEACAM-1, HMGB1, phosphatidylserine | Tumour | — (pre-clinical) | — |
LAG-3 | Activated T, NK cells, pDCs | MHCII | APC | LAG-3Ig fusion protein | Elevated clinical activity Phase I/II trial in combination with paclitaxel for metastatic breast carcinoma |
ICOS | Treg cells, activated T cells | ICOS-L | APC (especially activated pDCs) | MEDI-570 | Phase I Trial for T cell lymphoma (National Cancer Institute Clinical Trial NCT02520791) |
List of checkpoint inhibitors, their ligands, cell expression and clinical associations.
Immune checkpoints consist of a family of co-stimulatory and co-inhibitory receptors expressed by T cells that modulate their immune responses. Signalling from these receptors depends on their interaction with specific ligands present at the surface of various immune and non-immune cells. These regulatory pathways are a major cause of immune suppression during cancer due the high levels of co-inhibitory ligands being expressed in the tumour microenvironment, resulting in T cell immunosuppression. Monoclonal antibodies (mAb) blocking programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4), two co-inhibitory immune checkpoint receptors have become routine treatment against many malignancies and more therapeutic molecules against members of the immune checkpoint family are being trialled. Here we review the role of DC in the response to immune checkpoint therapies.
PD-1 is expressed by activated T cells and interacts with two ligands, PD-L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273). PD-1 engagement results in downregulation of T cell proliferation and function [117]. This inhibitory pathway is harnessed by tumour cells to escape attack by T cells through expression of PD-L1 on their cell surface. Anti-PD-1/PD-L1 therapies have shown considerable effects on patients with high PD-L1-expressing tumours, boosting the effector functions of tumour-associated CD8+ T cells inducing tumour regression. To date, two anti-PD-1 mAb (Pembrolizumab, Nivolumab) and three anti-PD-L1 mAb (Atezolizumab, Durvalumab, Avelumab) have been approved for the treatment of cancers including advanced melanoma, non-small-cell lung cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma and renal carcinoma [118].
The ligands for PD-1 are abundant on DC. PD-L1 expression is on pDC and cDC subsets and upregulated in response to inflammatory stimuli and following exposure to platinum-based chemotherapy drugs [84, 119]. Furthermore, PD-L1 is also highly expressed on DC that infiltrate tumours as exemplified by the high PD-L1 expression measured on both pDC and multiple myeloma cells isolated from the bone-marrow of multiple myeloma patients [120]. PD-L2 is detectable at low levels on cDC only after activation and is highly expressed by moDC [121]. Whether PD-L2 is also expressed by DC in different TMEs and the effect of anti-PD-L2 therapies is yet to be defined.
cDC1 play a critical role in the efficacy of anti-PD-1/PD-L1 mAb therapies. Single cell mass spectrometry analyses of PBMC from patients with advanced melanoma, before and after anti-PD-1 therapy revealed that CD141 and CD11c, both expressed by cDC1 are strong predictive biomarkers of clinical response to anti-PD-1 treatments [122]. This is consistent with several mouse studies reporting that cDC1-deficient mice do not respond to immune checkpoint blockade using anti-PD-L1 or a combination of anti-PD-1 anti-CTLA4 mAb [123, 124]. Furthermore, mice that possess cDC1 defective in antigen cross-presentation fail to establish CTL responses and do not respond to anti-PD-1 blockade [125].
The success of anti-PD-1 therapy also depends on a cross-talk between cDC1 and T cells in the TME. In mouse models anti-PD-1 treatment induces IL-12 production by tumour-infiltrating cDC1 [124, 126] which amplifies T cell effector functions. In melanoma patients, the clinical electroporation of an IL-12 plasmid in the tumour lesions enhances the CTL gene signature, thus validating the role of this cytokine in supporting CTL responses [126], Figure 1.
In addition to its ligands, expression of the PD-1 receptor on DC has been reported during cancer. In hepatocellular carcinoma patients, detectable levels of PD-1 were reported on peripheral blood cDC1, cDC2 and pDC whereas PD-1 was only present on cDC1 in healthy donors. This was confirmed with microscopy analyses of cancerous liver tissues showing co-expression of PD-1 and the DC marker CD11c [127]. In line with this data, co-expression of PD-1 and PD-L1 was detected on CD11c+ DC isolated from the tumours of non-small cell lung cancer patients [128]. However, in this case, PD-1 was absent from DC isolated from the PBMC of either cancer patients or healthy donors, suggesting that PD-1 is upregulated locally on DC in response to the immunosuppressive tumour environment [128].
Mouse studies support an inhibitory role of PD-1 on DC [127]. This finding however contrasts with a recent study revealing that PD-1 can establish
Combining anti-PD-1/PD-L1 therapy with DC-based vaccines, or vaccines that target DC
The co-inhibitory immune checkpoint CTLA4 (CD152) is constitutively expressed by regulatory T cells (Treg) and by effector T cells upon activation. CTLA4 is highly homologous to the co-stimulatory receptor CD28 and binds the same ligands CD80 and CD86 (B7.2), however with a much higher affinity. As such, CTLA4 outcompetes CD28 for ligand binding and reduces CD28-mediated co-stimulation of T cell functions. CTLA4 blockade promotes anti-tumour immunity by increasing the activation of effector T cells and by depleting Treg in the TME. The CTLA4 blocking mAb Ipilimumab and Tremelimumab have been approved for the treatment of metastatic melanoma, renal cell carcinoma and colorectal cancer [118].
CTLA4 on T cells directly alters DC functions by removing the CTLA4 ligands (CD80/86) from their cell surfaces. When human moDC are co-cultured with CTLA4+ T cells, CD80/86 levels on DC decrease rapidly in a CTLA4-dependent manner. This mechanism, named trans-endocytosis, involves the physical capture of CTLA4 ligands by the receptor and their degradation. This process is upregulated by TCR engagement [139, 140]. Mouse
Besides their regulation through CTLA4-CD80/86 interaction, moDC also express the CTLA4 molecule upon activation by TLR stimuli. Treatment of these cells with an agonistic anti-CTLA4 Ab induced increased production of IL-10, reduced expression of IL-8 and IL-12 and decreased T cell stimulation capacity [145]. MoDC are also able to secrete CTLA4 in extracellular microvesicles. Microvesicular CTLA4 has been shown to downregulate CD80 and CD86 on moDC [146].
Combinatorial approaches of anti-CTLA4 mAb with cancer vaccines have been tested in clinics and have yielded mixed results. In melanoma patients, peptide vaccines, in combination with anti-CTLA4 Ipilimumab did not show better clinical outcomes compared to Ipilimumab alone [127, 147, 148]. However, other strategies using DC vaccines have provided promising results. For instance, the co-administration to melanoma patients of autologous moDC that have been pulsed with tumour peptide, together with Tremelimumab, resulted in objective and durable tumour responses [149]. Furthermore, a phase II study using Ipilimumab and moDC electroporated with synthetic mRNA (TriMixDC-MEL) has been tested in advanced melanoma patients and has shown an encouraging rate of highly durable tumour response [150].
T cell immunoglobulin mucin-3 (TIM-3) is a co-inhibitory immune checkpoint receptor expressed by all T cell populations as well as B cells and a large variety of myeloid cells. Four TIM-3 ligands have been identified, including Galectin-9, CEACAM-1, HMGB1 and phosphatidylserine. Engagement of TIM-3 on tumour-infiltrating T cells induces exhaustion and suppresses tumour immunity. Preclinical studies have reported high therapeutic activities of blocking anti-TIM-3 antibodies against various types of malignancies and clinical trials with TIM-3 inhibitors are currently underway [128].
High TIM-3 expression has been reported on cDC1 and cDC2 from peripheral blood [151, 152, 153] and on tumour-associated cDC1 and cDC2 from mammary tumour biopsies [152]. Mouse models indicated that blocking TIM-3 on cDC1 leads to an increase in the T cell chemoattractant CXCL9. Moreover, cDC1 expressing TIM-3 correlated with CXCL9 expression in human breast cancer biopsies and was positively associated with CD8+ T cell infiltration. These data suggest that TIM-3 blocking in these cancers could potentially enhance CD8+ T cell recruitment to the TME [152].
Lymphocyte activation gene-3 (LAG-3) is a co-inhibitory immune checkpoint receptor expressed on activated T cells and NK cells that recognise MHCII molecules on APCs as a ligand. LAG3 negatively regulates T cell activation and is frequently co-expressed with PD-1 on exhausted T cells in the TME. Several LAG-3-targeting cancer immunotherapies are currently in different phases of clinical development [154].
The interaction between MHCII and LAG-3 not only has effects in T cells, but also induces reverse signalling in DCs that is stimulatory. This was shown using the soluble LAG-3-Ig fusion protein that activates moDC, as indicated by the upregulation of co-stimulatory molecules, the production of several pro-inflammatory cytokines and chemokines and increased allogenic T cell activation. However, Ab-mediated MHCII ligation does not activate moDC, thus showing that the MHCII: LAG-3 interaction is required in this process [155, 156, 157]. Soluble LAG-3-Ig fusion protein in combination with the chemotherapy drug Paclitaxel has demonstrated elevated clinical activity in metastatic breast carcinoma during a phase I/II trial. This treatment also strongly stimulated the patients’ APC, as evidenced by the increase in the number and activation of monocytes, pDC and cDCs [158].
Notably, LAG-3 itself has been found expressed by DC, specifically by a subpopulation of circulating pDC in healthy donors. LAG-3+ pDC are also found in the tumour lesions and in the tumour-draining lymph nodes of melanoma patients and are thought to contribute to the immunosuppressive environment. Engagement of LAG-3 on pDC provides an activating signal, independent of TLR signalling, inducing low IFN-α and high IL-6 expression [159]. Hence, LAG-3-specific mAb in cancer immunotherapies may enhance the anti-tumour immune response by inhibiting LAG-3 signalling in both T cells and DC.
Inducible T cell costimulatory (ICOS) belongs to the co-stimulatory immune checkpoint receptor family and similarly to CD28, enhances the proliferation and effector functions of T cells. ICOS is expressed on activated T cells and constitutively on a subpopulation of Treg [160] while ICOS-L is present at the surface of APC. High ICOS expression on T cells has been particularly observed during anti-CTLA4 therapies and the co-administration of agonistic ICOS-specific mAb further improves the efficacy to CTLA4 blockade [161].
pDC are able to induce immunosuppression though ICOS stimulation. ICOS-L is strongly upregulated by human blood pDC, but not CD11c+ cDC, in response to TLR stimuli or IL-3 [162]. Co-cultures of pDC with allogenic T cells induced IL-10 expression through a mechanism mediated by ICOS-L-ICOS interaction [162] and similar observations were reported with pDC isolated from ovarian carcinoma [163]. Furthermore, pDC are able to induce Treg proliferation though ICOS stimulation [160] and this mechanism likely explains the dramatic accumulation of ICOS+ Treg in ovarian, breast, liver and gastric tumour tissues, in close proximity with ICOS-L+ pDC [101, 164, 165, 166].
DCs are rare, heterogeneous cells with clear roles in anti-tumour immunity. As summarised in Figure 1, understanding how best to activate DC to gain optimal anti-tumour adaptive immune responses will likely involve careful optimisation of adjuvants, checkpoint immunotherapies and DC targeting strategies. Emerging studies will likely examine checkpoint receptors and their ligands on DC, lymphocytes and other cells in tumour environments, in order to design targeted therapies for optimal antigen presentation, DC activation and anti-tumour response.
Dendritic cells (DCs) are professional antigen presenting cells (APCs), the only cells capable of specifically activating naïve T cells and are key orchestrators of an immune response. They are a rare, heterogeneous population of haematopoietic cells that are equipped to capture, process and present antigen (Ag) to the adaptive immune system.
In a non-inflamed or steady state setting, DCs constantly sample the local environment for Ags and have the potential to induce peripheral tolerance via T cell anergy or deletion [1]. DCs recognise danger via pattern recognition receptors (PRR) on their cell surface, the cytoplasm and within cellular organelles [2]. Ligation of PRRs by pathogen associated molecular patterns (PAMPs) or damage associated molecular patterns (DAMPs), activates DC and licences DC to upregulate co-stimulatory marker expression such as CD86 and CD80 on their cell surface and initiate immunogenic T cell priming.
DCs situated in non-lymphoid tissues, also known as migratory DCs, constantly migrate to draining lymph nodes (LNs), maturing during this process, to present Ag to naïve T cells. Resident DCs in lymphoid organs are immature and maintain tolerance during steady state, but can stimulate naïve T cells when activated
In humans, the majority of DC characterisation studies are of DCs isolated from the blood due to the rarity of the cell type and limited access to human tissue samples, although more investigations on non-lymphoid DCs in the skin, lung and liver have recently emerged [4, 5, 6, 7]. DCs in the blood comprise ~1% of total peripheral blood mononuclear cells (PBMCs) and are traditionally identified by the high expression of MHCII (HLA-DR) and the lack of lineage markers CD3, CD14, CD15, CD19, CD20 and CD56, although the latter marker has recently been shown to be expressed on gut and other non-lymphoid DCs [6].
Human blood DCs can be divided into conventional DCs (cDCs) and plasmacytoid DCs (pDCs), which are HLA-DRhiCD11c+123− and HLA-DRhiCD11c−123+ respectively. Human blood cDCs are further categorised into cDC1 and cDC2 subsets. Additionally, there are monocyte-derived DCs that originate separately from cDCs and pDC precursors. The recent use of whole population and single cell sequencing techniques has been instrumental in elucidating transcription factors and surface markers that are unique to each DC subset, which has helped identify relationships between DC subsets across species and tissues as well as corroborate DC functional analyses [6, 7, 8, 9], summarised in Table 1.
DC subsets | |||
---|---|---|---|
cDC1 | cDC2 | pDC | |
Surface phenotype | CD11c+HLA-DR+ CD123−CLEC9A+ XCR1+Necl2+ CD141+ CD11b−CD172α− | CD11c+HLA-DR+CD123− CD1c+CD11b+CD172α+ CLEC10A+ with further subdivision based on CD5hiCD32B+CD163−CD36− or CD5loCD32B−CD163+CD36+ | CD11c−HLA-DR+ CD123+CD303+ CD304+CD45RA+ CD2+/− |
Transcription factors | |||
PRR expression | TLR3, 8 | TLR2, cytosolic RNA sensors (RIG-I, MDA-5), STING | TLR7, 9, STING |
Ag presentation | Cross-presentation of cellular Ag | Cross-presentation of soluble Ag | CD4+ and CD8+ T cell priming* |
Roles in immunity | Potent producer of Type III IFN (after TLR3 stimulation), CTL priming, Th1 response | Th1, Th17 response | Potent producers of Type I and III IFN and mediating anti-viral immunity |
Key features of human DC subsets.
Previous Ag presentation abilities by pDCs are now suggested to be contributed by contaminating AXL+Siglec6+ (AS) DCs.
cDC1s constitute ~0.03% of PBMCs and are found in the blood, tonsil, spleen and non-lymphoid tissues such as the skin. They were classically defined by the high expression of CD141 (blood DC antigen 3 (BDCA3) or thrombomodulin) [10]. However, CD141 is not a completely specific marker for cDC1 as it is also expressed on endothelial cells, monocytes and other DC subsets [8]. Using phenotypic, transcriptional and functional assays, these CD141+ DCs have been further characterised as CD11c+HLA-DR+CD11b−CD172a− CLEC9a+XCR1+Necl2+ cells that lack monocytic markers CD14 and CD16 [4, 11] identifying them as human cDC1 [12, 13, 14, 15, 16].
The dependence of CD141+ DCs on Flt3 ligand (FL), an important DC developmental factor, has been demonstrated
PRRs expressed by human cDC1s are predominantly Toll-like receptor (TLR) 3, located in endosomes and which recognises double-stranded RNA and TLR8, also located in endosomes and which recognises bacterial ssRNA and mammalian mitochondrial RNA [10, 22]. In response to TLR3 signals [23] and also HCV
The cDC1s are superior to other DC subsets in their ability to present ex
Human cDC2, traditionally known as CD1c+ or BDCA1+ DCs, constitute ~1% of PBMCs and can be identified by the expression of CD11c, CD11b, CD13, CD33, CD172a, HLA-DR and CD45RO [2, 10, 26]. The phenotypic similarities between these DCs and moDCs, as well as the expression of CD1c on B cells and other DC subsets, have made the precise segregation of this subset quite difficult. Although previous studies have used CD64 to exclude monocytes from bonafide CD1c+ DCs in the blood, cDCs express low levels of this marker and cannot be definitively used to separate the cell populations [6, 7]. More recently, the use of single cell RNA sequencing techniques has identified additional surface phenotypic markers, such as
The cDC2 DCs highly express TLR2 and also express a range of cytosolic viral RNA sensors such as RIG-I [30, 31]. Different proposed cDC2 subsets also seem to have different PRR expression patterns. For example, CD5hi cDC2 express high levels of TLR7 and 8 compared to CD5lo cDC2 and CD32B+ cDC2 express higher levels of
Activated cDC2s can drive Th17 immune response and can also produce high levels of IL-12p70, potentially inducing Th1 differentiation [2, 29]. However, current data suggests Th17 versus Th1 driven responses may be independently driven by CD5+ versus CD5lo cDC2 subsets, respectively [8, 28].
Human cDC2s are able to cross-present
The pDCs constitute ~0.01–0.04% of PBMCs and commonly reside in secondary lymphoid organs localising in the follicular cortex, T cell nodules and around high endothelial venules [36, 37]. As their name suggests, pDCs are similar in morphology to that of plasma cells. Under light microscopy, pDCs are observed to be spherical in shape with a rounded nucleus, often predominant endoplasmic reticulum and present as clusters in T-cell rich regions of lymphoid tissue [36, 37, 38].
The pDCs, originally identified as ‘natural interferon producing cells’ (NIPC), are renowned for their ability to drive immense type I and type III IFN production via TLRs 7 and 9 [39, 40, 41]. This IFN production is essential to combat viral infection but pDC-derived IFN is also thought to contribute to disease in autoimmune diseases including systemic lupus erythematosus [42]. They are also thought to play a role in Th2 induction and asthma progression in humans [42]. Conversely, pDC have also been shown to play a major role in tolerance
pDCs are recognised as being CD11c−/loCD45RA+CD123+CD303+CD304+HLA-DR+ and can express CD56 (reviewed in [2]). pDCs may also be identified by their transcription factors including; TCF4 (also known as E2-2), SPIB, ZEB2, IRF8, IRF7 and IRF4 [43, 44, 45]. Haploinsufficiency in the
The pDCs can be divided into 2 subsets based on CD2 expression [47]. Recent single cell transcriptomic profiling of blood DCs from healthy donors has revealed that CD2+ ‘pDC’ also express AXL and SIGLEC6 (known as AS DCs). These AS DCs can stimulate CD4+ and CD8+ allogeneic T cell proliferation whereas the segregation of pDCs away from contaminating AS DCs demonstrated potent IFN-α production after TLR9 stimulation and a lack of T cell priming attributes [8]. Whether AS DCs and pDC are 2 distinct cell types or differentiation stages of one another is yet to be defined.
A rare and highly aggressive acute leukaemia known as Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) involves the malignancy of pDC precursors [48], driven, at least in part by the juxtaposition of the pDC-specific RUNX2 enhancer and the MYC promotor due to the chromosomal translocation (6;8)(p21;q24) [49]. The BPDCN can be reliably identified by immunohistochemical staining with TCF4 and CD123 antibodies [50]. BPDCNs most commonly present as skin lesions and may be accompanied by swelling of other organs such as the lymph nodes, bone marrow or spleen. Standard chemotherapy treatments for myeloid neoplasms often result in poor prognosis [51] although a toxin-conjugated anti-CD123 drug, tagraxofusp-erzs, has recently been approved as the first FDA-approved BPDCN-specific treatment [52].
Monocyte derived DC (moDC) refers to DCs induced from monocytes with GM-CSF
It still remains unclear whether the moDC actually represent an
While the
The ability to present Ag and activate the adaptive immune response makes DCs an attractive target to re-invigorate anti-cancer immunity. There are different types of DC vaccines, with the most common type involving the
Thus far, a wide variety of moDC vaccine strategies have been trialled [68]. moDCs have been differentiated and matured using monocyte conditioned medium with various supplements of cytokines (TNF-α, GM-CSF, IL-4, IFN-α), TLR agonists (LPS) and other factors such as prostaglandin E2 [67, 68, 69]. There is also variety in the type of Ags loaded into DCs such as peptides from tumour-associated Ags (TAA), TAA-encoding mRNA and whole tumour lysates [67]. More recently, the electroporation of synthetic mRNA encoding DC-maturation factors such as CD40 ligand, constitutively active TLR4 and CD70 together with fusion proteins DC-LAMP and melanoma-associated Ags into autologous moDCs (TriMixDC-MEL) have proven safe and immunogenic in phase 1 clinical trials in metastatic melanoma [70]. However, the variation in the aforementioned vaccine factors as well as the route of DC administration (intranodal, i.v.) and lack of standardised method of moDC generation has shown variable efficacies of moDC vaccines in clinical outcomes.
More recent clinical trials using naturally circulating blood DCs have turned to CliniMACS system by Miltenyi to isolate different DC subsets from patients (Figure 1). Two completed Phase I clinical trials have used CD1c+ DCs (cDC2) loaded with TAA peptides in hormone refractory metastatic prostate cancer and metastatic melanoma and observed good safety and immunogenicity [71, 72]. Another completed Phase I trial using pDCs showed the induction of tumour-Ag specific CTL response as well as an IFN signature [33]. On-going clinical trials, as summarised by Bol et al., are not only isolating single DC subsets for vaccination, but are also trying combination vaccines comprised of cDC2 and pDC subsets and using dual-activating maturation agonists such as single stranded RNA that stimulates TLR8 on cDC2 and TLR7 on pDCs (NCT-02993315, NCT-02574377, NCT-02692976) [67]. However, there are still many challenges in using naturally circulating blood DCs in tumour vaccinations. The methodology for isolation of sufficient CD141+ cDC1 DCs, which comprise only 0.03% PBMCs, is still lacking and will be important to harness due to their superior ability to cross-present dead and necrotic Ag. Furthermore, although improved over the years, the duration of DCs spent
Overview of potential roles of DC in cancer therapies. To improve current cancer treatments and the activation of tumour-specific CTL, DC may be directly targeted
Apart from the
The tumour microenvironment (TME) is a complex niche of tumour cells, stromal cells and tumour infiltrating myeloid and lymphoid immune cells. The dynamic nature of this niche varies with different types and stages of cancer, as well as between patients themselves. It has been established that the infiltration of CD8+ cytotoxic T cells have been associated with better treatment outcomes with checkpoint blockade therapies in a number of cancer types including metastatic melanoma [83]. However, the phenotype and role of tumour-infiltrating DCs (TIDCs) are less clear, possibly due to the lack of consistent markers probing DCs within the TME and the lack of distinctions between monocyte and putative DC subsets [84].
Using immunohistochemistry staining, many studies have previously used CD1a and S100 proteins to identify TIDCs. The higher density of these cells within tumours correlated with better clinical outcomes in melanoma and head and neck cancers [84, 85]. However, discrepancies in this correlation were reported in colon, breast, gastric, nasopharyngeal, lung and ovarian cancers [84, 86, 87, 88]. One major factor that could explain these reported discrepancies is the markers used to identify DCs. CD1a and S100 are expressed at different levels on Langerhans cells (LCs), interdigitating DCs and moDCs, but not on cDCs or pDCs and the expression of these markers on epithelial-tropic DCs such as LCs could account for the strong correlations observed in only the epithelial cancers [84]. Furthermore, DC activation markers CD83 and DC-LAMP were used to identify mature DCs, though CD83 is not expressed in all DC subsets [7, 84, 89]. In breast adenocarcinoma patients, immature DCs were found to localise within the tumour whereas CD83/DC-LAMP+ mature DCs localised in the peri-tumour edges [90]. Some studies have reported significant correlations between the intratumoral infiltration of mature DCs with better clinical outcomes. For example, a recent report showed that the recruitment of DC-LAMPhi cells into the tumour stroma exhibited strong correlations with significantly higher overall and relapse-free survival in high-grade serous ovarian carcinoma [91]. However, this correlation has also been inconsistent in a number of different cancers [85, 90, 92, 93, 94].
More recently, with the establishment of The Cancer Genome Atlas (TCGA) program, scientists are able to compare DC-specific signatures with a publicly available molecular and clinical database of a vast array of cancers. In melanoma and breast cancer patients, DC-specific genes such as
Whilst the recent data above points towards a benefit of the infiltration of conventional DC into tumour sites, the correlation between tumour infiltrating pDCs and poor survival prognosis is clear. This has been described in breast, head and neck, ovarian and lung cancers [100, 101, 102, 103] where it is thought that pDC-induced tolerance and impaired IFN-α production contributes to a suppressive, non-immunogenic TME. Indeed mouse studies point to a role of TGF-β in the tumour environment in preventing an activatory phenotype of pDC and favouring a tolerising, IDO producing phenotype [104].
Further factors within the TME that have been illustrated to correlate with DC infiltration or function include for example, vascular endothelial growth factor (VEGF), a tumour angiogenic factor, inversely correlated with DC density and overall survival in gastric adenocarcinoma tissues [87, 105]. High serum VEGF levels were also associated with low blood cDC1 and cDC2 numbers in colorectal and non-small cell lung cancers and treatment of VEGF decoy receptor, VEGF-Trap, increased the proportion of mature DCs, but not overall numbers or DC priming function in various solid cancer patients [106, 107, 108]. Direct evidence of VEGF-induced DC inhibition was also reported in DCs differentiated from CD34+ precursors and moDCs [105, 106, 109]. Other cytokines such as IL-6, IL-10 and TGFβ have also demonstrated DC-inhibitory effects in the TME [104, 110, 111, 112, 113, 114].
In metastatic melanoma patients, higher active β-catenin signalling within the tumour was associated with low cDC1 signatures and T cell signatures [115]. Furthermore, the expression of fatty acid synthase was inversely correlated with CD11c+ DC signatures in ovarian, prostate and bladder cancers [116].
Chemotherapy and radiotherapy have remained the core pillars of cancer treatments. However, the combination of these traditional therapies with immunotherapies targeting immune checkpoint receptors has greatly enhanced patient clinical outcomes, especially in patients with immunogenic cancers, summarised in Table 2.
Checkpoint inhibitor (CI) | CI cell expression | Ligand | Ligand cell expression | Anti-CI mAb clinical name | Clinical outcome |
---|---|---|---|---|---|
PD-1 | T, B, NK cells, DC | PD-L1/2 | PD-L1: DC, monocytes, Treg, cells, tumour; PD-L2: Activated cDC, moDCs | Pembrolizumab, Nivolumab | Approved for metastatic melanoma, renal cell carcinoma, squamous-cell carcinoma of head and neck, Hodgkin’s lymphoma, metastatic colorectal, non-small cell lung, Merkel cell and ovarian cancers Improved clinical outcomes in combination with peptide/vector vaccines for advanced solid cancers, metastatic melanoma and HPV-16-related cancers |
CTLA4 | T cells, activated moDCs | CD80/86 (B7.1/2) | APC | Ipilimumab, Tremelimumab | Approved for metastatic melanoma, renal cell carcinoma and colorectal cancer treatments Mixed results in combination with peptide and moDC vaccines |
TIM-3 | T, B cells, cDC, myeloid cells | Galectin-9, CEACAM-1, HMGB1, phosphatidylserine | Tumour | — (pre-clinical) | — |
LAG-3 | Activated T, NK cells, pDCs | MHCII | APC | LAG-3Ig fusion protein | Elevated clinical activity Phase I/II trial in combination with paclitaxel for metastatic breast carcinoma |
ICOS | Treg cells, activated T cells | ICOS-L | APC (especially activated pDCs) | MEDI-570 | Phase I Trial for T cell lymphoma (National Cancer Institute Clinical Trial NCT02520791) |
List of checkpoint inhibitors, their ligands, cell expression and clinical associations.
Immune checkpoints consist of a family of co-stimulatory and co-inhibitory receptors expressed by T cells that modulate their immune responses. Signalling from these receptors depends on their interaction with specific ligands present at the surface of various immune and non-immune cells. These regulatory pathways are a major cause of immune suppression during cancer due the high levels of co-inhibitory ligands being expressed in the tumour microenvironment, resulting in T cell immunosuppression. Monoclonal antibodies (mAb) blocking programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4), two co-inhibitory immune checkpoint receptors have become routine treatment against many malignancies and more therapeutic molecules against members of the immune checkpoint family are being trialled. Here we review the role of DC in the response to immune checkpoint therapies.
PD-1 is expressed by activated T cells and interacts with two ligands, PD-L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273). PD-1 engagement results in downregulation of T cell proliferation and function [117]. This inhibitory pathway is harnessed by tumour cells to escape attack by T cells through expression of PD-L1 on their cell surface. Anti-PD-1/PD-L1 therapies have shown considerable effects on patients with high PD-L1-expressing tumours, boosting the effector functions of tumour-associated CD8+ T cells inducing tumour regression. To date, two anti-PD-1 mAb (Pembrolizumab, Nivolumab) and three anti-PD-L1 mAb (Atezolizumab, Durvalumab, Avelumab) have been approved for the treatment of cancers including advanced melanoma, non-small-cell lung cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma and renal carcinoma [118].
The ligands for PD-1 are abundant on DC. PD-L1 expression is on pDC and cDC subsets and upregulated in response to inflammatory stimuli and following exposure to platinum-based chemotherapy drugs [84, 119]. Furthermore, PD-L1 is also highly expressed on DC that infiltrate tumours as exemplified by the high PD-L1 expression measured on both pDC and multiple myeloma cells isolated from the bone-marrow of multiple myeloma patients [120]. PD-L2 is detectable at low levels on cDC only after activation and is highly expressed by moDC [121]. Whether PD-L2 is also expressed by DC in different TMEs and the effect of anti-PD-L2 therapies is yet to be defined.
cDC1 play a critical role in the efficacy of anti-PD-1/PD-L1 mAb therapies. Single cell mass spectrometry analyses of PBMC from patients with advanced melanoma, before and after anti-PD-1 therapy revealed that CD141 and CD11c, both expressed by cDC1 are strong predictive biomarkers of clinical response to anti-PD-1 treatments [122]. This is consistent with several mouse studies reporting that cDC1-deficient mice do not respond to immune checkpoint blockade using anti-PD-L1 or a combination of anti-PD-1 anti-CTLA4 mAb [123, 124]. Furthermore, mice that possess cDC1 defective in antigen cross-presentation fail to establish CTL responses and do not respond to anti-PD-1 blockade [125].
The success of anti-PD-1 therapy also depends on a cross-talk between cDC1 and T cells in the TME. In mouse models anti-PD-1 treatment induces IL-12 production by tumour-infiltrating cDC1 [124, 126] which amplifies T cell effector functions. In melanoma patients, the clinical electroporation of an IL-12 plasmid in the tumour lesions enhances the CTL gene signature, thus validating the role of this cytokine in supporting CTL responses [126], Figure 1.
In addition to its ligands, expression of the PD-1 receptor on DC has been reported during cancer. In hepatocellular carcinoma patients, detectable levels of PD-1 were reported on peripheral blood cDC1, cDC2 and pDC whereas PD-1 was only present on cDC1 in healthy donors. This was confirmed with microscopy analyses of cancerous liver tissues showing co-expression of PD-1 and the DC marker CD11c [127]. In line with this data, co-expression of PD-1 and PD-L1 was detected on CD11c+ DC isolated from the tumours of non-small cell lung cancer patients [128]. However, in this case, PD-1 was absent from DC isolated from the PBMC of either cancer patients or healthy donors, suggesting that PD-1 is upregulated locally on DC in response to the immunosuppressive tumour environment [128].
Mouse studies support an inhibitory role of PD-1 on DC [127]. This finding however contrasts with a recent study revealing that PD-1 can establish
Combining anti-PD-1/PD-L1 therapy with DC-based vaccines, or vaccines that target DC
The co-inhibitory immune checkpoint CTLA4 (CD152) is constitutively expressed by regulatory T cells (Treg) and by effector T cells upon activation. CTLA4 is highly homologous to the co-stimulatory receptor CD28 and binds the same ligands CD80 and CD86 (B7.2), however with a much higher affinity. As such, CTLA4 outcompetes CD28 for ligand binding and reduces CD28-mediated co-stimulation of T cell functions. CTLA4 blockade promotes anti-tumour immunity by increasing the activation of effector T cells and by depleting Treg in the TME. The CTLA4 blocking mAb Ipilimumab and Tremelimumab have been approved for the treatment of metastatic melanoma, renal cell carcinoma and colorectal cancer [118].
CTLA4 on T cells directly alters DC functions by removing the CTLA4 ligands (CD80/86) from their cell surfaces. When human moDC are co-cultured with CTLA4+ T cells, CD80/86 levels on DC decrease rapidly in a CTLA4-dependent manner. This mechanism, named trans-endocytosis, involves the physical capture of CTLA4 ligands by the receptor and their degradation. This process is upregulated by TCR engagement [139, 140]. Mouse
Besides their regulation through CTLA4-CD80/86 interaction, moDC also express the CTLA4 molecule upon activation by TLR stimuli. Treatment of these cells with an agonistic anti-CTLA4 Ab induced increased production of IL-10, reduced expression of IL-8 and IL-12 and decreased T cell stimulation capacity [145]. MoDC are also able to secrete CTLA4 in extracellular microvesicles. Microvesicular CTLA4 has been shown to downregulate CD80 and CD86 on moDC [146].
Combinatorial approaches of anti-CTLA4 mAb with cancer vaccines have been tested in clinics and have yielded mixed results. In melanoma patients, peptide vaccines, in combination with anti-CTLA4 Ipilimumab did not show better clinical outcomes compared to Ipilimumab alone [127, 147, 148]. However, other strategies using DC vaccines have provided promising results. For instance, the co-administration to melanoma patients of autologous moDC that have been pulsed with tumour peptide, together with Tremelimumab, resulted in objective and durable tumour responses [149]. Furthermore, a phase II study using Ipilimumab and moDC electroporated with synthetic mRNA (TriMixDC-MEL) has been tested in advanced melanoma patients and has shown an encouraging rate of highly durable tumour response [150].
T cell immunoglobulin mucin-3 (TIM-3) is a co-inhibitory immune checkpoint receptor expressed by all T cell populations as well as B cells and a large variety of myeloid cells. Four TIM-3 ligands have been identified, including Galectin-9, CEACAM-1, HMGB1 and phosphatidylserine. Engagement of TIM-3 on tumour-infiltrating T cells induces exhaustion and suppresses tumour immunity. Preclinical studies have reported high therapeutic activities of blocking anti-TIM-3 antibodies against various types of malignancies and clinical trials with TIM-3 inhibitors are currently underway [128].
High TIM-3 expression has been reported on cDC1 and cDC2 from peripheral blood [151, 152, 153] and on tumour-associated cDC1 and cDC2 from mammary tumour biopsies [152]. Mouse models indicated that blocking TIM-3 on cDC1 leads to an increase in the T cell chemoattractant CXCL9. Moreover, cDC1 expressing TIM-3 correlated with CXCL9 expression in human breast cancer biopsies and was positively associated with CD8+ T cell infiltration. These data suggest that TIM-3 blocking in these cancers could potentially enhance CD8+ T cell recruitment to the TME [152].
Lymphocyte activation gene-3 (LAG-3) is a co-inhibitory immune checkpoint receptor expressed on activated T cells and NK cells that recognise MHCII molecules on APCs as a ligand. LAG3 negatively regulates T cell activation and is frequently co-expressed with PD-1 on exhausted T cells in the TME. Several LAG-3-targeting cancer immunotherapies are currently in different phases of clinical development [154].
The interaction between MHCII and LAG-3 not only has effects in T cells, but also induces reverse signalling in DCs that is stimulatory. This was shown using the soluble LAG-3-Ig fusion protein that activates moDC, as indicated by the upregulation of co-stimulatory molecules, the production of several pro-inflammatory cytokines and chemokines and increased allogenic T cell activation. However, Ab-mediated MHCII ligation does not activate moDC, thus showing that the MHCII: LAG-3 interaction is required in this process [155, 156, 157]. Soluble LAG-3-Ig fusion protein in combination with the chemotherapy drug Paclitaxel has demonstrated elevated clinical activity in metastatic breast carcinoma during a phase I/II trial. This treatment also strongly stimulated the patients’ APC, as evidenced by the increase in the number and activation of monocytes, pDC and cDCs [158].
Notably, LAG-3 itself has been found expressed by DC, specifically by a subpopulation of circulating pDC in healthy donors. LAG-3+ pDC are also found in the tumour lesions and in the tumour-draining lymph nodes of melanoma patients and are thought to contribute to the immunosuppressive environment. Engagement of LAG-3 on pDC provides an activating signal, independent of TLR signalling, inducing low IFN-α and high IL-6 expression [159]. Hence, LAG-3-specific mAb in cancer immunotherapies may enhance the anti-tumour immune response by inhibiting LAG-3 signalling in both T cells and DC.
Inducible T cell costimulatory (ICOS) belongs to the co-stimulatory immune checkpoint receptor family and similarly to CD28, enhances the proliferation and effector functions of T cells. ICOS is expressed on activated T cells and constitutively on a subpopulation of Treg [160] while ICOS-L is present at the surface of APC. High ICOS expression on T cells has been particularly observed during anti-CTLA4 therapies and the co-administration of agonistic ICOS-specific mAb further improves the efficacy to CTLA4 blockade [161].
pDC are able to induce immunosuppression though ICOS stimulation. ICOS-L is strongly upregulated by human blood pDC, but not CD11c+ cDC, in response to TLR stimuli or IL-3 [162]. Co-cultures of pDC with allogenic T cells induced IL-10 expression through a mechanism mediated by ICOS-L-ICOS interaction [162] and similar observations were reported with pDC isolated from ovarian carcinoma [163]. Furthermore, pDC are able to induce Treg proliferation though ICOS stimulation [160] and this mechanism likely explains the dramatic accumulation of ICOS+ Treg in ovarian, breast, liver and gastric tumour tissues, in close proximity with ICOS-L+ pDC [101, 164, 165, 166].
DCs are rare, heterogeneous cells with clear roles in anti-tumour immunity. As summarised in Figure 1, understanding how best to activate DC to gain optimal anti-tumour adaptive immune responses will likely involve careful optimisation of adjuvants, checkpoint immunotherapies and DC targeting strategies. Emerging studies will likely examine checkpoint receptors and their ligands on DC, lymphocytes and other cells in tumour environments, in order to design targeted therapies for optimal antigen presentation, DC activation and anti-tumour response.
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Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Bacterial Infectious Diseases",value:3,count:2},{group:"subseries",caption:"Parasitic Infectious Diseases",value:5,count:4},{group:"subseries",caption:"Viral Infectious Diseases",value:6,count:7}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:250,paginationItems:[{id:"274452",title:"Dr.",name:"Yousif",middleName:"Mohamed",surname:"Abdallah",slug:"yousif-abdallah",fullName:"Yousif Abdallah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274452/images/8324_n.jpg",biography:"I certainly enjoyed my experience in Radiotherapy and Nuclear Medicine, particularly it has been in different institutions and hospitals with different Medical Cultures and allocated resources. Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:{name:"Medical University Plovdiv",country:{name:"Bulgaria"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Igor Victorovich Lakhno was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics, and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"243698",title:"Dr.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:null,institution:null},{id:"7227",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Matsui",slug:"hiroaki-matsui",fullName:"Hiroaki Matsui",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Tokyo",country:{name:"Japan"}}},{id:"312999",title:"Dr.",name:"Bernard O.",middleName:null,surname:"Asimeng",slug:"bernard-o.-asimeng",fullName:"Bernard O. Asimeng",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}}]}},subseries:{item:{id:"15",type:"subseries",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11411,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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