Open access peer-reviewed chapter

Highlighting the Role of DC-NK Cell Interplay in Immunobiology and Immunotherapy

Written By

João Calmeiro, Mylene Carrascal, Célia Gomes, Amílcar Falcão, Maria Teresa Cruz and Bruno Miguel Neves

Submitted: 30 January 2018 Reviewed: 18 May 2018 Published: 05 November 2018

DOI: 10.5772/intechopen.78804

From the Edited Volume

Dendritic Cells

Edited by Svetlana P. Chapoval

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Dendritic cells (DCs) and natural killer (NK) cells are both part of the innate immune system, also playing crucial functions in the regulation of adaptive immune responses. In recent years, numerous works have demonstrated that DCs and NK cells mutually influence each other with major consequences in the type and effectiveness of elicited immune responses. Among other effects, DC-NK crosstalk can result in NK cell activation and DC maturation or deletion, depending on its activation status. In this chapter and after a brief overview of DCs and NK immunobiology, we focus on the process of DC-NK crosstalk, highlighting the relevance of rationally exploring this interplay in the development of more effective cancer immunotherapies.


  • dendritic cells
  • natural killer cells
  • DC-NK crosstalk
  • cancer
  • immunotherapy

1. Introduction

Dendritic cells (DCs) are a heterogeneous population of innate immune cells with unique capacity to process and present antigens to naïve T cells. They are, therefore, responsible for the orchestration of the adaptive immune responses, promoting either immunity or tolerance to self-antigens [1]. Given these unique characteristics, DCs have for long been used in clinical approaches, particularly to boost antitumor immune response during cancer treatment [2]. The results gathered from more than 20 years of experimentation and almost 350 clinical trials demonstrated that DC-based antitumor immunotherapy is safe and with relevant clinical outcomes [3].

One of the key observations from these experiments is that the success of DC-based vaccines relies not only on the capacity of these cells to polarize and activate T lymphocytes but also on their ability to bidirectionally interact with natural killer (NK) cells. In fact, it is known that an optimal antitumor immune response depends on a complex interplay between CD8+ T cells, CD4+ T cells and NK cells [4]. NK cells are large granular innate immune cells with cytotoxic functions. They are crucial for the initial defense against viral infections, destroying infected cells and also for the elimination of tumor cells or foreign and endogenous cells under stress [5]. The complex cell-to-cell crosstalk between DCs and NK cells has major consequences on the modulation of immune responses. Therefore, it is expected that the rational design of new DC-based immunotherapies encompasses this required interplay with NK cells in order to synergistically evoke a superior clinical outcome [6].

In this chapter, we focus on several key aspects: the DC and NK immunobiology, the mechanisms and consequences of DC-NK bidirectional crosstalk, and the potential and relevance of DC-NK crosstalk in cancer immunotherapy.


2. Dendritic cells

2.1. Dendritic cells at a glance

DCs were first described by Paul Langerhans in 1868, being erroneously characterized as part of peripheral nervous system. It took almost 100 years to reveal the real functions of these cells. In 1973 and subsequent years, Ralph Steinman and Zanvil Cohn demonstrated by a series of elegant experiments that DCs are crucial regulators of both innate and acquired arms of the immune system [7, 8]. These cells have the unparalleled ability to polarize naïve T lymphocytes into their different effector or regulatory subsets and are potent enhancers of NK cell cytotoxicity [9, 10] as well as fundamental accessory cells in the production of primary antibody responses [11]. They also take part in the preservation of tolerance to antigens, with thymus DCs helping in the shaping of the T cell repertoire through the deletion of autoreactive lymphocytes [12, 13].

Classically, DCs are found in an immature state at locations of possible antigen entry such as the skin and mucosal surfaces (e.g., genitourinary, gastrointestinal, and respiratory systems), as well as in the connective tissue of all solid organs and even in fat tissue, retina, and brain [8, 14, 15, 16, 17, 18]. Upon encountering a potential threat, DCs capture and process it, displaying the resultant antigens on major histocompatibility complex (MHC)-I or MHC-II molecules. During this process, DCs engage a program, termed maturation, characterized by several morphological, phenotypical and functional changes that strongly increase their immunogenic profile. Then, mature DCs enter draining lymphatic vessels and migrate to lymph nodes where they present processed antigens to naïve T lymphocytes, generating a specific immune response [19].

2.2. Dendritic cell subsets and characteristics

DCs are composed of a very heterogeneous family of innate immune cells with characteristics frequently overlapping between subpopulations, making hard to define an unambiguous classification. Hence, in 2014, a novel classification system was created, first centered on DC ontogeny and then on their location, function, and phenotype [20].

Concerning ontogeny, all DC subpopulations are derived from a common hematopoietic CD34+ stem cell precursor that originates multiple intermediate precursors, which differentiate into several DC subsets in a process that is highly dependent on hematopoietic cytokines and growth factors [8, 14, 21]. There are three major subpopulations of DCs: plasmacytoid DCs (pDCs) characterized by the expression of CD123, CD303, CD304, FCER1, ILT3, and ILT7; classical DCs 1 (cDC1) that express CD141, CLEC9A, XCR1, and CADM1; and classical DCs 2 expressing CD1c, CD11c, CD11b, CD2, FCER1, SIRPA, ILT1, and CLEC4A [2, 22, 23].

cDCs1 are 10 times less frequent than cDCs2 and can be found in the blood, lymph nodes, tonsil, spleen, bone marrow, and in non-lymphoid tissues such as skin, lung, intestine, and liver. Functionally, they are characterized by a high capacity to cross-present antigens via MHC class I to CD8+T cells, promoting their activation to cytotoxic T lymphocytes (CTLs) [24]. Although they secrete low amounts of IL-12 when compared to cDCs2 [25, 26], they are highly effective in promoting Th1 cell polarization and NK cell activation. This is in part due to the expression of the chemokine receptor XCR1, which enables cDCs1 to closely interact with XCL-producing cells such as activated T lymphocytes and NK cells [25, 26, 27, 28]. cDCs1 are particularly equipped for the recognition of viral and intracellular antigens: they express TLR3, TLR9, and TLR10, also being major producers of type III interferons IFN λ 1–3 [29].

Regarding myeloid cDCs2, they are the major DC population being found in blood, spleen, skin, lung, and intestine. They express a large panel of pattern recognition receptors (PRRs) namely TLRs 2, 4, 5, 6, and 8, NOD-like receptors (NOD2, NLRP1, NLRP3, and NAIP), and lectin receptors such as DEC205, CLEC4A, CLEC6A, CLEC7A, CLEC10A, CLEC12A, and also the asialoglycoprotein receptor. Once activated, cDCs2 produce high amounts of IL-12 and also secrete IL-1, IL-6, IL-8, IL-10, IL-23, and tumor necrosis factor-alpha (TNF-α) [25, 30]. The different blood and tissue resident cDCs2 orchestrate a wide range of immune responses against viral, bacterial, fungal, and helminthic infections as a consequence of their capacity to polarize naïve T cells toward Th1, Th2, Th17, Th22, and CTL effector populations [30, 31, 32].

pDCs present a further limited distribution, being mainly found in blood and T cell areas of lymphoid organs. This DC subset is specifically tailored to sense and respond to viral infections [2, 8, 14, 33]. Indeed, pDCs highly express TLR7 and TLR9, the sensors for single-stranded RNA and double-stranded DNA, respectively [34], and upon activation, they produce high quantities of type I and III interferons, TNF-α, IL-6, and granzyme B [35]. Due to their intrinsic capacity to cross-present antigens to CD8+ T cells, they also play a relevant role in antitumor immunity [36].

Finally, Langerhans cells, the main DCs found in the skin epidermis, are CD45+, MHC-II+, positive for Langerin, and have a low expression of CD11c and a high expression of CD1a. They are exclusively derived from embryonic precursors and are able to self-renew locally [37]. At a functional level, Langerhans cells can induce immunogenic or tolerogenic responses upon specific maturation stimuli and cellular microenvironment and are particularly effective in antigen cross-presentation [38].

The phenotypical and functional characterization of human DC subsets is an exciting area that remains in continuous evolution. It is conceivable that this increased knowledge in DC immunobiology will empower their use in the design of more rational and effective immunotherapies.


3. NK cells

3.1. NK cell immunobiology

NK cells represent 5–15% of the circulating lymphocytes and play a pivotal role in host defense against pathogens and cancer [5]. Although recognized for their spontaneous killing ability of virus-infected or transformed cells without prior immunization, these cells also play an important role in the modulation of immune responses through the secretion of multiple cytokines and chemokines [39]. Additionally, a growing body of evidence suggests that NK cells can mediate antigen-specific immunological memory, associated with adaptive immunity [40].

NK cell activity is tightly regulated by a complex array of germline-encoded activating and inhibitory receptors randomly generated during NK cell differentiation and maturation [41]. The integration of the signals transmitted by these receptors forms the basis of NK cell reactivity to their targets and determines the magnitude of NK cell–mediated cytotoxicity and cytokine production. The inhibitory receptors such as killer immunoglobulin-like receptors (KIRs) and the lectin-like CD94/NKG2A heterodimer recognize self-molecules of the major histocompatibility complex (MHC) class I expressed in almost all healthy cell types and protect themselves from NK cell-mediated killing [42]. Paradoxically, the engagement of MHC class I molecules maintains NK cells in a state of responsiveness to subsequent activation, a property referred to as NK cell licensing [43]. During the course of tumorigenesis or viral infection, cells often decrease or even lose the expression of MHC class I molecules and upregulate the expression of a wide spectrum of stress-induced surface ligands that are recognized by activating receptors in NK cells, including the natural cytotoxic receptors (NCRs: NKp46, NKp30, and NKp44), the C-type lectin receptors (CD94/NKG2C, NKG2D, NKG2E/H, and NKG2F), DNAM-1, and killer immunoglobulin-like receptors with a short cytoplasmic tail (KIRs, KIR-2DS, and KIR-3DS) [41, 44]. When multiple of these activating receptors are simultaneously engaged and reach a threshold that surpass the inhibitory signals, NK cells are shifted to an activated phenotype, exerting their cytolytic activity against target cells [41, 45]. Several cytokines have been described to activate and promote NK cells antitumor activity. The common gamma chain (γc) family of cytokines, like IL-2, IL-12, IL-15, IL-18 and IL-21, are the most well-recognized ILs to boost NK cell antitumor activities and have been used to improve the proliferation, differentiation and effector function of NK cells [46].

Regarding their cytolytic activity, the perforin/granzyme pathway is the main mechanism used by NK cells to kill target cells. Upon activation, NK cells polarize the lytic granules to the immunological synapse formed with the target cell and release the membrane disrupting perforin that forms transient pores on the target cell membrane, allowing the entrance of granzymes, a family of serine proteases, that trigger an apoptotic-like cell death [47]. The death receptor pathways involving FasL and TRAIL are also employed by NK cells on target cell-induced apoptosis through a perforin-independent mechanism. Death receptor members of the TNF-α family such as FAS and the death receptor 5 (DR5) are usually upregulated in tumor cells and transduce apoptotic signals upon binding to their cognate ligands FasL and TRAIL on NK cells, resulting in a classical caspase-dependent apoptosis [48]. NK cells are also mediators of the antibody-dependent cellular cytotoxicity (ADCC), another type of granule-mediated cell death that occurs when the Fc receptor expressed by NK cells (FcγRIII or CD16) binds to the Fc portion of IgG1 antibodies-coated target cells [49]. This interaction results in a strong activation signal that overcomes the inhibitory signals, leading to a downstream cascade of activation events with the release of cytolytic granules and inflammatory mediators.

In addition to the direct cytotoxic mechanisms, NK cells also act as immunomodulatory cells engaged in reciprocal interactions with DCs, macrophages, and T cells through the release of various cytokines, chemokines and growth factors, which might augment or dampen immune responses [50].


4. DC-NK cell interplay

Currently, it is clear that DCs and NK cells have a crucial role in modulating innate and adaptive immune responses through a complex cell-to-cell crosstalk (Figure 1). Indeed, DC-mediated activation of NK cells contributes to the development of potent innate immunity, whereas, in turn, activated NK cells provide signals for DC activation, maturation, and cytokine production, promoting adaptive immunity [6]. This DC-NK crosstalk occurs, in vivo, in the lymph nodes [51, 52], at the sites of inflammation, in peripheral tissues such as the skin and mucosa [53] and in solid tumor microenvironments [54].

Figure 1.

Dendritic cell-natural killer cell interplay. iDCs can undergo maturation by exposure to several stimuli, pathogen-associated molecular patterns (PAMPs), and IFN. The resulting mDCs secrete IL-12, IL-18, IL-15 and type I IFN, which in turn induce the proliferation and activation of NK cells, leading to further secretion of IFN-γ. NK-DC interaction by NKG2D with MICA/B and CXC3CR1 with CXC3CL1 can also lead to NK cell activation. Thus, activated NK cells are able to increase DC maturation, dependent on cytokines like IFN-γ and TNF-α, as well as the interaction of NKp30 receptor on NK cells with its ligand on DCs. On the other hand, activated NK cells can also eliminate MHC-I low-expressing iDCs by cell contact-dependent interactions of NKp30 receptor with NKp30 ligand and DNAM-1 with Nectin-2 or PVR. iDCs, immature dendritic cells; IFN, interferon; mDCs, mature dendritic cells.

4.1. Activation of NK cells by DCs

Several studies have demonstrated the potential of DCs to influence the function of NK cells. Seminal works revealed a reduction of NK cell-dependent antitumor effects in mice depleted from CD8α DCs, suggesting a direct role of DCs in NK cells activation [55]. The triggering of NK cells by DCs seems to be dependent on both cell-to-cell contact and soluble factors. Accordingly, in human and animal studies, NK cells activation by DCs was significantly disrupted by transwell separation, reinforcing a major contribution of cell-to-cell contact to this close communication [55, 56]. Further studies have demonstrated that DC-produced IL-12 is also crucial for NK cells activation, namely for their production of IFN-γ [57]. This process comprises the formation of stimulatory synapses between DCs and NK cells, which promote the polarized secretion of pre-assembled stores of IL-12 by DCs toward NK cells [58]. Furthermore, Poly(I:C)-treated DCs and IFN-α-treated DCs also induce NK cells to secrete IFN-γ by the binding of activating NK cell receptor NKG2D to its specific ligands, such as MHC class I-related chains A and B (MICA/B) [59, 60]. Another relevant interaction that results in NK cell cytotoxicity and IFN-γ release occurs between CXC3CL1 expressed on DCs and CXC3CR1 on NK cells [61].

IL-15 can be considered as an additional and important cytokine involved in the process of DC-mediated activation of NK cells. This cytokine can be found bounded to DCs membrane and is able to induce NK cell proliferation, survival, and to enhance their cytotoxic functions [57, 62]. Additionally, in DCs, transmembrane TNF, as well as membrane-bound IL-15, can enhance NK cells proliferation, CD69 expression, and IFN-γ secretion [63]. Both signaling mechanisms are mediated by cell-to-cell contact via simultaneous engagement of DCs transmembrane TNF and membrane-bound IL-15, with their respective NK cell receptors, leading to its activation. Furthermore, NK cells proliferation is also dependent on the interaction between CD40 and B7 molecules on DCs with CD40L and CD28 on NK cells, respectively [64].

IL-18 expressed by immature and mature DCs has also been implicated in NK cells activation. DC-derived IL-18, as well as IL-12, is involved in the upregulation of NK cell cytotoxicity [56]. Similar to IL-12, IL-18 seems to be delivered in secretory lysosomes at the NK/DC synaptic cleft, leading to NK cells activation [65]. In case of regulatory DCs, their insufficient production of IL-18 is involved in the restrained IFN-γ secretion by NK cells, downregulating NK cells activation [66]. In addition, studies performed in mice revealed that both IL-18 and IL-12 are also involved in the expansion of Ly49H+ NK cells promoted by CD8α+ DCs [67].

The role of type I IFN (IFN-α/β) on NK cell activation has also been assessed during NK-DCs crosstalk. Type I IFN, secreted by plasmacytoid DCs [68], is required for NK cell cytotoxicity in response to virus infection [69, 70]. In the context of TLR stimulation, NK cells priming is dependent on the recognition of type I IFN signals by DCs and on the subsequent production and trans-presentation of IL-15 by DCs to resting NK cells [71]. Finally, IL-2 produced by bacterially activated myeloid DCs has also been shown to be required, both in vitro and in vivo, for NK cells activation and IFN-γ-efficient production [72].

4.2. DC modulation by activated NK cells

Over the last two decades, multiple studies have reported that NK cells play a relevant role in the DCs maturation process, either by killing DCs that did not properly acquire a mature phenotype or through direct DCs stimulation [73]. The process of immature DC lysis is dependent on NK-activating receptors as well as on the amount of MHC class I molecules on DCs [74, 75]. In vitro assays have demonstrated that activated NK cells can recognize and kill DCs via NKp30 natural cytotoxicity receptor, suggesting the expression of a still unknown NKp30 ligand on DCs surface. Mature DCs are susceptible to NK cell killing when NK inhibitory signal is blocked by MCH-I antibodies, confirming that mature DCs are naturally spared due to their high expression of MHC class I molecules [76]. In addition, DNAM-1-triggering receptor and its ligands, poliovirus receptor (PVR) and Nectin-2, have been demonstrated to be crucial in NK cell-mediated lysis of immature DCs. DNAM-1 receptor on NK cells cooperates with NKp30 receptor in the NK-mediated elimination of DCs. The degree of contribution of DNAM-1 appeared to correlate with the surface amount of its specific ligands PVR and Nectin-2 on DCs [77]. Other in vivo studies have also shown that NK cells efficiently kill injected immature bone marrow-derived DCs, via a pathway dependent on the TNF-related apoptosis-inducing ligand (TRAIL) [78]. Similarly, another study confirmed that NK cells can kill incompletely matured DCs in the context of a viral infection via TRAIL—Death Receptor 4 (DR4) pathway [79]. These findings led to the hypothesis that the killing of immature DCs by NK cells should promote the survival of the most immunogenic DCs, supporting and empowering efficient and protective immune responses. In fact, it has been demonstrated that the killing of immature DCs by autologous NK cells is particularly important for the expansion of cancer-specific CTLs [80].

On the other hand, in chronic viral infections, IL-10 produced by NK cells induces contrasting phenotypic changes in DCs; specifically, immature DCs exhibit aberrant resistance to NK cell-mediated elimination, whereas mature DCs had an increased susceptibility to NKG2D-dependent elimination. This process leads to the accumulation of poorly immunogenic DCs in lymph nodes, causing a progressive immune dysfunction [81]. Furthermore, DC lysis by NK cells can also negatively regulate the duration and effectiveness of virus-specific T cell responses in vivo by limiting the exposure of T cells to infected antigen-presenting cells, which negatively impacts the quality of T cell responses and their ability to limit viral persistence [82]. Additionally, it has been shown that in solid organ transplantation, host NK cells kill allogeneic DCs via the perforin pathway. This will limit allogeneic antigen presentation to host lymphocytes, reducing T cell–mediated graft-versus-host disease [83].

Activated NK cells can also improve DCs maturation and activation, enhancing their ability to stimulate T cell responses. When NK cells are cultured with immature DCs in the presence of maturation stimuli, such as lipopolysaccharide (LPS), they strongly enhance DCs maturation, specifically by upregulating the DCs co-stimulatory molecule CD86 and IL-12 production. NK cells activated by IL-2 are also able to induce DCs maturation, improving their ability to stimulate allogeneic naïve CD4+ T cells. These effects of NK cells on DCs maturation are cell contact dependent, although the secretion of IFN-γ and TNF-α is also relevant [84, 85]. These findings show that both effects of NK cells on DCs (DC killing and stimulation) are dependent on NKp30-triggering receptor.

Further studies have shown that NK cell-activated DCs produce higher levels of IL12p70 after subsequent CD40 ligands stimulation, leading to an increase in the induction of T cell responses [86, 87]. The effect of NK cells on DCs is also dependent on the type of NK cell activation; IL-2-primed “effector” NK cells can kill DCs, whereas IL-18-primed NK cells are just prone to enhance the ability of DCs to produce IL-12p70 dependent on CD40L stimulation [88]. In fact, NK cells are able to trigger immature DCs to secrete IL-18 through a Ca2+-dependent and tubulin-mediated recruitment of IL-18-containing secretory lysosomes toward the adhering NK cell. Then, IL18-activated NK cells secrete the pro-inflammatory “danger signal” high-mobility group B1 (HMGB1), which induces DC maturation and protects DCs from lysis, thus favoring the development of adaptive immune responses [65]. Furthermore, human NK cells, exposed to different cytokines, are able to promote distinct pathways of Th1 priming. Specifically, IL-12- or IL-2-activated NK cells induce maturation of DCs capable of priming IFN-γ-producing Th1 cells, whereas IL-18-conditioned NK cells induce Th1 polarization only when co-cultured with both DCs and T cells, which release IL-12 and IL-2, respectively, promoting IFN-γ production. Thus, the local prevalence of IL-12, IL-2, and IL-18 at the inflammatory sites may differentially modulate the NK cell interaction with DCs, leading to different outcomes in naïve T cell polarization [89].

Recently, IL-23 was uncovered as an enhancer of NK cell ability to stimulate DCs. IL-23 induces NK cells activation and displays a synergistic effect with IL-18 for IFN-γ production by NK cells. This cytokine also potentiates the increase of CD86 expression and IL-12 secretion by LPS-treated DCs upon IL-18-stimulated NK cells contact [90].


5. DCs and NK cells in cancer immunotherapy

The main purpose of cancer immunotherapy is to change the balance from tumor escape or equilibrium to cancer cells elimination. Latest developments have been focused at increasing the activation status of the innate and adaptive immune systems, comprising cytokine administration, Car T cells, DCs and NK-based vaccines, checkpoint inhibitors and monoclonal antibodies engineered to target high-yield elements in oncogenic-signaling pathways [91]. A crucial point for the development of such approaches was the definition of the optimal characteristics of an antitumor immune response. Specifically, it became evident that this response depends on a complex cells interplay involving DCs, CD8+ T cells, CD4+ T cells, and NK cells.

Given their positioning at the interface between innate and adaptive immunities and their unparalleled capacity to interact and modulate immune effector cells, DCs have been scrutinized and settled as highly desirable and full of translational and clinical potential. Since the 1990s, DCs have been used in more than 350 clinical trials as cellular antitumor vaccines [3]. Currently, there are three approaches exploring DCs in oncologic treatments: (1) non-targeted protein and nucleic acids-based vaccines captured by DCs in vivo; (2) direct targeting of antigens to DCs in vivo; and (3) vaccines composed of ex vivo-generated DCs matured and loaded with tumor antigens [19]. Notwithstanding the good safety profile of antitumor DC-based vaccines, the rate of success in inducing clear therapeutic outcomes is inconsistent [3]. Objective tumor responses are usually above 15% [92], and promising vaccines in early-phase studies [93, 94] often fail to present clinical benefits in pivotal phase III trials [95]. Differentiation of DCs ex vivo from blood monocytes followed by their injection back into the patient is by far the most common strategy [1, 8]. This approach suffers from some limitations: very few of the injected DCs migrate to the lymph nodes to present antigens to T cells, and it became evident that monocyte-derived DCs are functionally limited when compared to endogenous DCs subpopulations [96, 97].In vivo targeting of antigens to specific DC subsets, tailoring of ex vivo differentiated DCs to particular phenotypes, and the combination of DCs-based vaccines with other antitumor therapies are critical steps for the effective success of new DCs immunotherapies [2, 3, 4, 92].

As referred in the earlier section, NK cells can directly eliminate tumor cells and indirectly enhance antitumor adaptive immunity by favoring DCs maturation and by killing immature DCs, thus enhancing immunogenic DC populations that will polarize antigen-specific CTLs [76, 98]. Importantly, the cell debris resultant from NK tumor cell destruction is also an important source of multiple tumor antigens for DCs cross-presentation to CD8+ T cells [99]. Due to these characteristics, NK cells have been clinically explored in recent years in several immunotherapeutic strategies for cancer. There are mainly two therapeutic approaches based on NK cells: the use of NK cell stimulants/modulators to take advantage of endogenous responses and the adoptive cell transfers of fully differentiated and ex vivo-activated NK cells [100, 101]. The adoptive cell transfers of autologous NK cells have been tested and well tolerated in the treatment of several cancers, including glioma, lymphoma, and renal cell carcinoma, though clinical responses have not always been observed [102, 103].


6. Future perspectives

In parallel with the growing knowledge on immune cells and cancer biology, cell-based immunotherapies must be tailored to answer the new demands. Whereas initial research focused on generating mainly tumor CTLs responses, it becomes clear that the activation of multiple immune effector cells is the key to success for curative cancer vaccination.

Apart from CTL induction, DC-NK cell crosstalk is of major importance in antitumor immune responses [4]. Efficient DC-vaccine-mediated antitumor immunity has been shown to be strongly dependent on NK cell activity [6]. This was highlighted by experiments where NK cell depletion drastically impacted tumor elimination following DC vaccination [104, 105]. Moreover, data from several clinical trials on DC-based antitumor vaccines indicate that positive outcomes seem to correlate with high levels of activated NK cells in responder patients [106].

Taken together, these data underscore why future research efforts should also focus on optimizing the NK cell–interacting properties of DC vaccines, in addition to improving their T cell–stimulatory capacity. The NK cell–activating character of DC vaccine preparations can be imprinted at multiple levels, such as by (1) tailoring the phenotype of ex vivo differentiated DCs, (2) using specific DCs subsets, and (3) targeting endogenous DCs populations that are intrinsically prone to interact with NK cells. The former approach includes the use of DCs expressing high levels of IL-12 and IL-15 [107] or manipulated to express the receptor XCR1. On the other hand, the other potential strategy is to target endogenous DCs subsets expressing XCR1. By using/targeting XCR1 expressing DCs, we potentiate their interaction with activated CD8+T cells and NK cell, given that these are the main producers of the XCR1 ligand XCL1 (Figure 2) [26, 27, 108].

Figure 2.

DC-NK cell crosstalk in cancer. NK cells can be activated by DCs, directly by cell contact and/or by DC-produced cytokines such as IL-12, IL-15 and IL18. Activated NK cells can then proliferate and secrete cytokines like IFN-γ, which will stimulate antitumor-acquired immune response. Specifically, IFN-γ induces CD8+ T cells to convert into antigen-specific CTLs and supports the creation of immunological memory against the tumor antigens. Additionally, IFN-γ can also stimulate the polarization of CD4+ T cells into Th1 subset that in turn stimulates CTL differentiation. Furthermore, activated NK cells, additionally to induce DCs maturation, will destroy tumor cells, fueling DCs with tumor antigens that are then cross-presented to CD8+ T cells. The cDCs1 population (CD141+ XCRI+) is particularly effective in this interplay: The expression of XCR1 receptor by this DC subset and of its ligand XCL1 by T and NK cells during infectious and inflammatory responses potentiates the interaction between these cells. Additionally, CD141+ XCRI+ DCs present an exceptional antigen cross-presentation capacity and are producers of high amounts of IL-12 following activation. CD-40 L, CD-40 ligand; IFN-γ, interferon γ; IL, interleukin; TAA, tumor-associated antigens; TCR, T cell receptor; XCL1, chemokine (C motif) ligand; XCR1, chemokine receptor for XCL1.

In conclusion, the design of new DC-based vaccination strategies should encompass NK cell-stimulating potency. Additionally, it would be of great value to systematically incorporate NK cells monitoring as an outcome in antitumor DC-based clinical trials.



This work was financed by the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme: project CENTRO-01-0145-FEDER-000012-HealthyAging2020, the COMPETE 2020—Operational Programme for Competitiveness and Internationalization, and the Portuguese national funds via FCT—Fundação para a Ciência e a Tecnologia, I.P.: project POCI-01-0145-FEDER-007440.


Conflict of interest

The authors declare no conflict of interest.


  1. 1. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245-252. DOI: 10.1038/32588
  2. 2. Sabado RL, Balan S, Bhardwaj N. Dendritic cell-based immunotherapy. Cell Research. 2017;27:74-95. DOI: 10.1038/cr.2016.157
  3. 3. Constantino J, Gomes C, Falcão A, Cruz MT, Neves BM. Antitumor dendritic cell–based vaccines: Lessons from 20 years of clinical trials and future perspectives. Translational Research. 2016;168:74-95. DOI: 10.1016/j.trsl.2015.07.008
  4. 4. Lion E, Smits ELJM, Berneman ZN, Van Tendeloo VFI. NK cells: Key to success of DC-based cancer vaccines? The Oncologist. 2012;17:1256-1270. DOI: 10.1634/theoncologist.2011-0122
  5. 5. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nature Immunology. 2008;9:503-510. DOI: 10.1038/ni1582
  6. 6. Pampena MB, Levy EM. Natural killer cells as helper cells in dendritic cell cancer vaccines. Frontiers in Immunology. 2015;6:13. DOI: 10.3389/fimmu.2015.00013
  7. 7. Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. The Journal of Experimental Medicine. 1973;137:1142-1162
  8. 8. Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature, Publ. Online. 27 Sept. 2007;449:419. DOI: 10.1038/NATURE06175
  9. 9. Larsen SK, Gao Y, Basse PH. NK cells in the tumor microenvironment. Critical Reviews in Oncogenesis. 2014;19:91-105
  10. 10. Cheng M, Chen Y, Xiao W, Sun R, Tian Z. NK cell-based immunotherapy for malignant diseases. Cellular & Molecular Immunology. 2013;10:230-252. DOI: 10.1038/cmi.2013.10
  11. 11. Inaba K, Steinman RM, Van Voorhis WC, Muramatsu S. Dendritic cells are critical accessory cells for thymus-dependent antibody responses in mouse and in man. Proceedings of the National Academy of Sciences of the United States of America. 1983;80:6041-6045
  12. 12. Hopp A-K, Rupp A, Lukacs-Kornek V. Self-antigen presentation by dendritic cells in autoimmunity. Frontiers in Immunology. 2014;5:55. DOI: 10.3389/fimmu.2014.00055
  13. 13. Klein L, Kyewski B, Allen PM, Hogquist KA. Positive and negative selection of the T cell repertoire: What thymocytes see (and don’t see). Nature Reviews. Immunology. 2014;14:377-391. DOI: 10.1038/nri3667
  14. 14. Van Brussel I, Berneman ZN, Cools N. Optimizing dendritic cell-based immunotherapy: Tackling the complexity of different arms of the immune system. Mediators of Inflammation. 2012;2012:1-14. DOI: 10.1155/2012/690643
  15. 15. Hashimoto D, Miller J, Merad M. Dendritic cell and macrophage heterogeneity in vivo. Immunity. 2011;35:323-335. DOI: 10.1016/j.immuni.2011.09.007
  16. 16. Sundara Rajan S, Longhi MP. Dendritic cells and adipose tissue. Immunology. 2016;149:353-361. DOI: 10.1111/imm.12653
  17. 17. D’Agostino PM, Gottfried-Blackmore A, Anandasabapathy N, Bulloch K. Brain dendritic cells: Biology and pathology. Acta Neuropathologica. 2012;124:599-614. DOI: 10.1007/s00401-012-1018-0
  18. 18. Lehmann U, Heuss ND, McPherson SW, Roehrich H, Gregerson DS. Dendritic cells are early responders to retinal injury. Neurobiology of Disease. 2010;40:177-184. DOI: 10.1016/j.nbd.2010.05.022
  19. 19. Palucka K, Banchereau J. Dendritic-cell-based therapeutic cancer vaccines. Immunity. 2013;39:38-48. DOI: 10.1016/j.immuni.2013.07.004
  20. 20. Guilliams M, Ginhoux F, Jakubzick C, Naik SH, Onai N, Schraml BU, Segura E, Tussiwand R, Yona S. Dendritic cells, monocytes and macrophages: A unified nomenclature based on ontogeny. Nature Reviews. Immunology. 2014;14:571-578. DOI: 10.1038/nri3712
  21. 21. Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: Ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annual Review of Immunology. 2013;31:563-604. DOI: 10.1146/annurev-immunol-020711-074950
  22. 22. Collin M, Bigley V. Human dendritic cell subsets: An update. Immunology. 2018;154:3-20. DOI: 10.1111/imm.12888
  23. 23. Poltorak MP, Schraml BU. Fate mapping of dendritic cells. Frontiers in Immunology. 2015;6:199. DOI: 10.3389/fimmu.2015.00199
  24. 24. Jongbloed SL, Kassianos AJ, McDonald KJ, Clark GJ, Ju X, Angel CE, Chen C-JJ, Dunbar PR, Wadley RB, Jeet V, Vulink AJE, Hart DNJ, Radford KJ. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. The Journal of Experimental Medicine. 2010;207:1247-1260. DOI: 10.1084/jem.20092140
  25. 25. Nizzoli G, Krietsch J, Weick A, Steinfelder S, Facciotti F, Gruarin P, Bianco A, Steckel B, Moro M, Crosti M, Romagnani C, Stolzel K, Torretta S, Pignataro L, Scheibenbogen C, Neddermann P, De Francesco R, Abrignani S, Geginat J. Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T-cell responses. Blood. 2013;122:932-942. DOI: 10.1182/blood-2013-04-495424
  26. 26. Bachem A, Güttler S, Hartung E, Ebstein F, Schaefer M, Tannert A, Salama A, Movassaghi K, Opitz C, Mages HW, Henn V, Kloetzel P-M, Gurka S, Kroczek RA. Superior antigen cross-presentation and XCR1 expression define human CD11c+ CD141+ cells as homologues of mouse CD8+ dendritic cells. The Journal of Experimental Medicine. 2010;207:1273-1281. DOI: 10.1084/jem.20100348
  27. 27. Ohta T, Sugiyama M, Hemmi H, Yamazaki C, Okura S, Sasaki I, Fukuda Y, Orimo T, Ishii KJ, Hoshino K, Ginhoux F, Kaisho T. Crucial roles of XCR1-expressing dendritic cells and the XCR1-XCL1 chemokine axis in intestinal immune homeostasis. Scientific Reports. 2016;6:23505. DOI: 10.1038/srep23505
  28. 28. Alexandre YO, Ghilas S, Sanchez C, Le Bon A, Crozat K, Dalod M. XCR1+ dendritic cells promote memory CD8+ T cell recall upon secondary infections with Listeria monocytogenes or certain viruses. The Journal of Experimental Medicine. 2016;213:75-92. DOI: 10.1084/jem.20142350
  29. 29. Lauterbach H, Bathke B, Gilles S, Traidl-Hoffmann C, Luber CA, Fejer G, Freudenberg MA, Davey GM, Vremec D, Kallies A, Wu L, Shortman K, Chaplin P, Suter M, O’Keeffe M, Hochrein H. Mouse CD8α+ DCs and human BDCA3+ DCs are major producers of IFN-λ in response to poly IC. The Journal of Experimental Medicine. 2010;207:2703-2717. DOI: 10.1084/jem.20092720
  30. 30. Sittig SP, Bakdash G, Weiden J, Sköld AE, Tel J, Figdor CG, de Vries IJM, Schreibelt G. A comparative study of the T cell stimulatory and polarizing capacity of human primary blood dendritic cell subsets. Mediators of Inflammation. 2016;2016:1-11. DOI: 10.1155/2016/3605643
  31. 31. Di Blasio S, Wortel IMN, van Bladel DAG, de Vries LE, Duiveman-de Boer T, Worah K, de Haas N, Buschow SI, de Vries IJM, Figdor CG, Hato SV. Human CD1c+ DCs are critical cellular mediators of immune responses induced by immunogenic cell death. Oncoimmunology. 2016;5:e1192739. DOI: 10.1080/2162402X.2016.1192739
  32. 32. Yin X, Yu H, Jin X, Li J, Guo H, Shi Q, Yin Z, Xu Y, Wang X, Liu R, Wang S, Zhang L. Human blood CD1c + dendritic cells encompass CD5high and CD5low subsets that differ significantly in phenotype, gene expression, and functions. Journal of Immunology. 2017;198:1553-1564. DOI: 10.4049/jimmunol.1600193
  33. 33. Stockwin LH, McGonagle D, Martin IG, Blair GE. Dendritic cells: Immunological sentinels with a central role in health and disease. Immunology and Cell Biology. 2000;78:91-102. DOI: 10.1046/j.1440-1711.2000.00888.x
  34. 34. Bao M, Liu Y-J. Regulation of TLR7/9 signaling in plasmacytoid dendritic cells. Protein & Cell. 2013;4:40-52. DOI: 10.1007/s13238-012-2104-8
  35. 35. Swiecki M, Colonna M. The multifaceted biology of plasmacytoid dendritic cells. Nature Reviews. Immunology. 2015;15:471-485. DOI: 10.1038/nri3865
  36. 36. Lou Y, Liu C, Kim GJ, Liu Y-J, Hwu P, Wang G. Plasmacytoid dendritic cells synergize with myeloid dendritic cells in the induction of antigen-specific antitumor immune responses. Journal of Immunology. 2007;178:1534-1541. DOI: 10.4049/JIMMUNOL.178.3.1534
  37. 37. Kanitakis J, Morelon E, Petruzzo P, Badet L, Dubernard J. Self-renewal capacity of human epidermal langerhans cells: Observations made on a composite tissue allograft. Experimental Dermatology. 2011;20(2):145-146. DOI: 10.1111/j.1600-0625.2010.01146.x
  38. 38. Malissen B, Tamoutounour S, Henri S. The origins and functions of dendritic cells and macrophages in the skin. Nature Reviews. Immunology. 2014;14:417-428. DOI: 10.1038/nri3683
  39. 39. Huntington ND, Vosshenrich CAJ, Di Santo JP. Developmental pathways that generate natural-killer-cell diversity in mice and humans. Nature Reviews. Immunology. 2007;7:703-714. DOI: 10.1038/nri2154
  40. 40. Sun JC, Beilke JN, Lanier LL. Adaptive immune features of natural killer cells. Nature. 2009;457:557-561. DOI: 10.1038/nature07665
  41. 41. Long EO, Sik Kim H, Liu D, Peterson ME, Rajagopalan S. Controlling natural killer cell responses: Integration of signals for activation and inhibition. Annual Review of Immunology. 2013;31:227-258. DOI: 10.1146/annurev-immunol-020711-075005
  42. 42. Long EO. Negative signaling by inhibitory receptors: The NK cell paradigm. Immunological Reviews. 2008;224:70-84. DOI: 10.1111/j.1600-065X.2008.00660.x
  43. 43. Raulet DH, Vance RE. Self-tolerance of natural killer cells. Nature Reviews. Immunology. 2006;6:520-531. DOI: 10.1038/nri1863
  44. 44. Lanier LL. Activating and Inhibitory NK Cell Receptors. Boston, MA: Springer; 1998. pp. 13-18. DOI: 10.1007/978-1-4615-5355-7_2
  45. 45. Bryceson YT, March ME, Ljunggren H-G, Long EO. Activation, coactivation, and costimulation of resting human natural killer cells. Immunological Reviews. 2006;214:73-91. DOI: 10.1111/j.1600-065X.2006.00457.x
  46. 46. Romee R, Leong JW, Fehniger TA. Utilizing cytokines to function-enable human NK cells for the immunotherapy of cancer. Scientifica (Cairo). 2014;2014:1-18. DOI: 10.1155/2014/205796
  47. 47. Voskoboinik I, Smyth MJ, Trapani JA. Perforin-mediated target-cell death and immune homeostasis. Nature Reviews. Immunology. 2006;6:940-952. DOI: 10.1038/nri1983
  48. 48. Screpanti V, Wallin RP, Ljunggren HG, Grandien A. A central role for death receptor-mediated apoptosis in the rejection of tumors by NK cells. Journal of Immunology. 2001;167:2068-2073
  49. 49. Wang W, Erbe AK, Hank JA, Morris ZS, Sondel PM. NK cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Frontiers in Immunology. 2015;6:368. DOI: 10.3389/fimmu.2015.00368
  50. 50. Sungur CM, Murphy WJ. Positive and negative regulation by NK cells in cancer. Critical Reviews in Oncogenesis. 2014;19:57-66
  51. 51. Celli S, Breart B, Bousso P. Intravital two-photon imaging of natural killer cells and dendritic cells in lymph nodes. In: Innate Immunity. Totowa, NJ: Humana Press; 2008. pp. 119-126. DOI: 10.1007/978-1-59745-570-1_7
  52. 52. Bajénoff M, Breart B, Huang AYC, Qi H, Cazareth J, Braud VM, Germain RN, Glaichenhaus N. Natural killer cell behavior in lymph nodes revealed by static and real-time imaging. The Journal of Experimental Medicine. 2006;203:619-631. DOI: 10.1084/jem.20051474
  53. 53. Buentke E, Heffler LC, Scheynius A, Wilson JL, Wallin RPA, Löfman C, Chambers BJ, Ljunggren H-G. Natural killer and dendritic cell contact in lesional atopic dermatitis skin–Malassezia-influenced cell interaction. The Journal of Investigative Dermatology. 2002;119:850-857. DOI: 10.1046/j.1523-1747.2002.00132.x
  54. 54. Mocikat R, Braumüller H, Gumy A, Egeter O, Ziegler H, Reusch U, Bubeck A, Louis J, Mailhammer R, Riethmüller G, Koszinowski U, Röcken M. Natural killer cells activated by MHC class I(low) targets prime dendritic cells to induce protective CD8 T cell responses. Immunity. 2003;19:561-569
  55. 55. Fernandez NC, Lozier A, Flament C, Ricciardi-Castagnoli P, Bellet D, Suter M, Perricaudet M, Tursz T, Maraskovsky E, Zitvogel L. Dendritic cells directly trigger NK cell functions: Cross-talk relevant in innate anti-tumor immune responses in vivo. Nature Medicine. 1999;5:405-411. DOI: 10.1038/7403
  56. 56. Yu Y, Hagihara M, Ando K, Gansuvd B, Matsuzawa H, Tsuchiya T, Ueda Y, Inoue H, Hotta T, Kato S. Enhancement of human cord blood CD34+ cell-derived NK cell cytotoxicity by dendritic cells. Journal of Immunology. 2001;166:1590-1600
  57. 57. Ferlazzo G, Pack M, Thomas D, Paludan C, Schmid D, Strowig T, Bougras G, Muller WA, Moretta L, Munz C. Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs. Proceedings of the National Academy of Sciences. 2004;101:16606-16611. DOI: 10.1073/pnas.0407522101
  58. 58. Borg C, Jalil A, Laderach D, Maruyama K, Wakasugi H, Charrier S, Ryffel B, Cambi A, Figdor C, Vainchenker W, Galy A, Caignard A, Zitvogel L. NK cell activation by dendritic cells (DCs) requires the formation of a synapse leading to IL-12 polarization in DCs. Blood. 2004;104:3267-3275. DOI: 10.1182/blood-2004-01-0380
  59. 59. Jinushi M, Takehara T, Kanto T, Tatsumi T, Groh V, Spies T, Miyagi T, Suzuki T, Sasaki Y, Hayashi N. Critical role of MHC class I-related chain A and B expression on IFN-alpha-stimulated dendritic cells in NK cell activation: Impairment in chronic hepatitis C virus infection. Journal of Immunology. 2003;170:1249-1256
  60. 60. Draghi M, Pashine A, Sanjanwala B, Gendzekhadze K, Cantoni C, Cosman D, Moretta A, Valiante NM, Parham P. NKp46 and NKG2D recognition of infected dendritic cells is necessary for NK cell activation in the human response to influenza infection. Journal of Immunology. 2007;178:2688-2698
  61. 61. Pallandre JR, Krzewski K, Bedel R, Ryffel B, Caignard A, Rohrlich PS, Pivot X, Tiberghien P, Zitvogel L, Strominger JL, Borg C. Dendritic cell and natural killer cell cross-talk: A pivotal role of CX3CL1 in NK cytoskeleton organization and activation. Blood. 2008;112:4420-4424. DOI: 10.1182/blood-2007-12-126888
  62. 62. Anguille S, Van Acker HH, Van den Bergh J, Willemen Y, Goossens H, Van Tendeloo VF, Smits EL, Berneman ZN, Lion E. Interleukin-15 dendritic cells harness NK cell cytotoxic effector function in a contact- and IL-15-dependent manner. PLoS One. 2015;10:e0123340. DOI: 10.1371/journal.pone.0123340
  63. 63. Vujanovic L, Szymkowski DE, Alber S, Watkins SC, Vujanovic NL, Butterfield LH. Virally infected and matured human dendritic cells activate natural killer cells via cooperative activity of plasma membrane-bound TNF and IL-15. Blood. 2010;116:575-583. DOI: 10.1182/blood-2009-08-240325
  64. 64. Amakata Y, Fujiyama Y, Andoh A, Hodohara K, Bamba T. Mechanism of NK cell activation induced by coculture with dendritic cells derived from peripheral blood monocytes. Clinical and Experimental Immunology. 2001;124:214-222. DOI: 10.1046/J.1365-2249.2001.01550.X
  65. 65. Semino C, Angelini G, Poggi A, Rubartelli A. NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1. Blood. 2005;106:609-616. DOI: 10.1182/blood-2004-10-3906
  66. 66. Spallanzani RG, Torres NI, Avila DE, Ziblat A, Iraolagoitia XLR, Rossi LE, Domaica CI, Fuertes MB, Rabinovich GA, Zwirner NW. Regulatory dendritic cells restrain NK cell IFN-γ production through mechanisms involving NKp46, IL-10, and MHC class I–specific inhibitory receptors. Journal of Immunology. 2015;195:2141-2148. DOI: 10.4049/jimmunol.1403161
  67. 67. Andrews DM, Scalzo AA, Yokoyama WM, Smyth MJ, Degli-Esposti MA. Functional interactions between dendritic cells and NK cells during viral infection. Nature Immunology. 2003;4:175-181. DOI: 10.1038/ni880
  68. 68. Vremec D, O’Keeffe M, Hochrein H, Fuchsberger M, Caminschi I, Lahoud M, Shortman K. Production of interferons by dendritic cells, plasmacytoid cells, natural killer cells, and interferon-producing killer dendritic cells. Blood. 2006;109:1165-1173. DOI: 10.1182/blood-2006-05-015354
  69. 69. Martinez J, Huang X, Yang Y. Direct action of type I IFN on NK cells is required for their activation in response to vaccinia viral infection in vivo. Journal of Immunology. 2008;180:1592-1597
  70. 70. Nguyen KB, Salazar-Mather TP, Dalod MY, Van Deusen JB, Wei X, Liew FY, Caligiuri MA, Durbin JE, Biron CA. Coordinated and distinct roles for IFN-alpha beta, IL-12, and IL-15 regulation of NK cell responses to viral infection. Journal of Immunology. 2002;169:4279-4287
  71. 71. Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A. Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity. 2007;26:503-517. DOI: 10.1016/j.immuni.2007.03.006
  72. 72. Granucci F, Zanoni I, Pavelka N, van Dommelen SLH, Andoniou CE, Belardelli F, Degli Esposti MA, Ricciardi-Castagnoli P. A contribution of mouse dendritic cell–derived IL-2 for NK cell activation. The Journal of Experimental Medicine. 2004;200:287-295. DOI: 10.1084/jem.20040370
  73. 73. Ferlazzo G, Semino C, Melioli G. HLA class I molecule expression is up-regulated during maturation of dendritic cells, protecting them from natural killer cell-mediated lysis. Immunology Letters. 2001;76:37-41. DOI: 10.1016/S0165-2478(00)00323-0
  74. 74. Ferlazzo G. Natural killer and dendritic cell liaison: Recent insights and open questions. Immunology Letters. 2005;101:12-17. DOI: 10.1016/j.imlet.2005.04.015
  75. 75. Piccioli D, Sbrana S, Melandri E, Valiante NM. Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. The Journal of Experimental Medicine. 2002;195:335-341
  76. 76. Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Münz C. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. The Journal of Experimental Medicine. 2002;195:343-351
  77. 77. Pende D, Castriconi R, Romagnani P, Spaggiari GM, Marcenaro S, Dondero A, Lazzeri E, Lasagni L, Martini S, Rivera P, Capobianco A, Moretta L, Moretta A, Bottino C. Expression of the DNAM-1 ligands, nectin-2 (CD112) and poliovirus receptor (CD155), on dendritic cells: Relevance for natural killer-dendritic cell interaction. Blood. 2006;107:2030-2036. DOI: 10.1182/blood-2005-07-2696
  78. 78. Hayakawa Y, Screpanti V, Yagita H, Grandien A, Ljunggren H-G, Smyth MJ, Chambers BJ. NK cell TRAIL eliminates immature dendritic cells in vivo and limits dendritic cell vaccination efficacy. Journal of Immunology. 2004;172:123-129
  79. 79. Melki M-T, Saïdi H, Dufour A, Olivo-Marin J-C, Gougeon M-L. Escape of HIV-1-infected dendritic cells from TRAIL-mediated NK cell cytotoxicity during NK-DC cross-talk–A pivotal role of HMGB1. PLoS Pathogens. 2010;6:e1000862. DOI: 10.1371/journal.ppat.1000862
  80. 80. Morandi B, Mortara L, Chiossone L, Accolla RS, Mingari MC, Moretta L, Moretta A, Ferlazzo G. Dendritic cell editing by activated natural killer cells results in a more protective cancer-specific immune response. PLoS One. 2012;7:e39170. DOI: 10.1371/journal.pone.0039170
  81. 81. Alter G, Kavanagh D, Rihn S, Luteijn R, Brooks D, Oldstone M, van Lunzen J, Altfeld M. IL-10 induces aberrant deletion of dendritic cells by natural killer cells in the context of HIV infection. The Journal of Clinical Investigation. 2010;120:1905-1913. DOI: 10.1172/JCI40913
  82. 82. Andrews DM, Estcourt MJ, Andoniou CE, Wikstrom ME, Khong A, Voigt V, Fleming P, Tabarias H, Hill GR, van der Most RG, Scalzo AA, Smyth MJ, Degli-Esposti MA. Innate immunity defines the capacity of antiviral T cells to limit persistent infection. The Journal of Experimental Medicine. 2010;207:1333-1343. DOI: 10.1084/jem.20091193
  83. 83. Laffont S, Seillet C, Ortaldo J, Coudert JD, Guery J-C. Natural killer cells recruited into lymph nodes inhibit alloreactive T-cell activation through perforin-mediated killing of donor allogeneic dendritic cells. Blood. 2008;112:661-671. DOI: 10.1182/blood-2007-10-120089
  84. 84. Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G. Reciprocal activating interaction between natural killer cells and dendritic cells. The Journal of Experimental Medicine. 2002;195:327-333
  85. 85. Vitale M, Della Chiesa M, Carlomagno S, Pende D, Aricò M, Moretta L, Moretta A. NK-dependent DC maturation is mediated by TNFalpha and IFNgamma released upon engagement of the NKp30 triggering receptor. Blood. 2005;106:566-571. DOI: 10.1182/blood-2004-10-4035
  86. 86. Mailliard RB, Son Y-I, Redlinger R, Coates PT, Giermasz A, Morel PA, Storkus WJ, Kalinski P. Dendritic cells mediate NK cell help for Th1 and CTL responses: Two-signal requirement for the induction of NK cell helper function. Journal of Immunology. 2003;171:2366-2373
  87. 87. Langers I, Renoux V, Reschner A, Touzé A, Coursaget P, Boniver J, Koch J, Delvenne P, Jacobs N. Natural killer and dendritic cells collaborate in the immune response induced by the vaccine against uterine cervical cancer. European Journal of Immunology. 2014;44:3585-3595. DOI: 10.1002/eji.201444594
  88. 88. Mailliard RB, Alber SM, Shen H, Watkins SC, Kirkwood JM, Herberman RB, Kalinski P. IL-18-induced CD83+CCR7+ NK helper cells. The Journal of Experimental Medicine. 2005;202:941-953. DOI: 10.1084/jem.20050128
  89. 89. Agaugue S, Marcenaro E, Ferranti B, Moretta L, Moretta A. Human natural killer cells exposed to IL-2, IL-12, IL-18, or IL-4 differently modulate priming of naive T cells by monocyte-derived dendritic cells. Blood. 2008;112:1776-1783. DOI: 10.1182/blood-2008-02-135871
  90. 90. Ziblat A, Nuñez SY, Raffo Iraolagoitia XL, Spallanzani RG, Torres NI, Sierra JM, Secchiari F, Domaica CI, Fuertes MB, Zwirner NW. Interleukin (IL)-23 stimulates IFN-γ secretion by CD56bright natural killer cells and enhances IL-18-driven dendritic cells activation. Frontiers in Immunology. 2018;8:1959. DOI: 10.3389/fimmu.2017.01959
  91. 91. Campbell AM, Decker RH. Mini-review of conventional and hypofractionated radiation therapy combined with immunotherapy for non-small cell lung cancer. Translational Lung Cancer Research; 6(2017):220-229. DOI: 10.21037/tlcr.2017.03.02
  92. 92. Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapy. The Lancet Oncology. 2014;15:e257-e267. DOI: 10.1016/S1470-2045(13)70585-0
  93. 93. Vansteenkiste J, Zielinski M, Linder A, Dahabreh J, Gonzalez EE, Malinowski W, Lopez-Brea M, Vanakesa T, Jassem J, Kalofonos H, Perdeus J, Bonnet R, Basko J, Janilionis R, Passlick B, Treasure T, Gillet M, Lehmann FF, Brichard VG. Adjuvant MAGE-A3 immunotherapy in resected non–small-cell lung cancer: Phase II randomized study results. Journal of Clinical Oncology. 2013;31:2396-2403. DOI: 10.1200/JCO.2012.43.7103
  94. 94. Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, Nawrocki S, Ciuleanu T-E, Bosquée L, Trigo JM, Spira A, Tremblay L, Nyman J, Ramlau R, Wickart-Johansson G, Ellis P, Gladkov O, Pereira JR, Eberhardt WEE, Helwig C, Schröder A, Shepherd FA, START Trial Team. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): A randomised, double-blind, phase 3 trial. The Lancet Oncology. 2014;15:59-68. DOI: 10.1016/S1470-2045(13)70510-2
  95. 95. Okamoto M, Kobayashi M, Yonemitsu Y, Koido S, Homma S. Dendritic cell-based vaccine for pancreatic cancer in Japan. World Journal of Gastrointestinal Pharmacology and Therapeutics. 2016;7:133. DOI: 10.4292/WJGPT.V7.I1.133
  96. 96. Ali OA, Huebsch N, Cao L, Dranoff G, Mooney DJ. Infection-mimicking materials to program dendritic cells in situ. Nature Materials. 2009;8:151-158. DOI: 10.1038/nmat2357
  97. 97. Kleindienst P, Brocker T. Endogenous dendritic cells are required for amplification of T cell responses induced by dendritic cell vaccines in vivo. Journal of Immunology. 2003;170:2817-2823
  98. 98. Ferlazzo G, Münz C. NK cell compartments and their activation by dendritic cells. Journal of Immunology. 2004;172:1333-1339. DOI: 10.4049/JIMMUNOL.172.3.1333
  99. 99. Deauvieau F, Ollion V, Doffin A-C, Achard C, Fonteneau J-F, Verronese E, Durand I, Ghittoni R, Marvel J, Dezutter-Dambuyant C, Walzer T, Vie H, Perrot I, Goutagny N, Caux C, Valladeau-Guilemond J. Human natural killer cells promote cross-presentation of tumor cell-derived antigens by dendritic cells. International Journal of Cancer. 2015;136:1085-1094. DOI: 10.1002/ijc.29087
  100. 100. Ames E, Murphy WJ. Advantages and clinical applications of natural killer cells in cancer immunotherapy. Cancer Immunology, Immunotherapy. 2014;63:21-28. DOI: 10.1007/s00262-013-1469-8
  101. 101. Hallett WHD, Murphy WJ. Positive and negative regulation of natural killer cells: Therapeutic implications. Seminars in Cancer Biology. 2006;16:367-382. DOI: 10.1016/j.semcancer.2006.07.003
  102. 102. Dillman RO, Duma CM, Schiltz PM, DePriest C, Ellis RA, Okamoto K, Beutel LD, De Leon C, Chico S. Intracavitary placement of autologous lymphokine-activated killer (LAK) cells after resection of recurrent glioblastoma. Journal of Immunotherapy. 2004;27:398-404
  103. 103. Burns LJ, Weisdorf DJ, DeFor TE, Vesole DH, Repka TL, Blazar BR, Burger SR, Panoskaltsis-Mortari A, Keever-Taylor CA, Zhang M-J, Miller JS. IL-2-based immunotherapy after autologous transplantation for lymphoma and breast cancer induces immune activation and cytokine release: A phase I/II trial. Bone Marrow Transplantation. 2003;32:177-186. DOI: 10.1038/sj.bmt.1704086
  104. 104. Bouwer AL, Saunderson SC, Caldwell FJ, Damani TT, Pelham SJ, Dunn AC, Jack RW, Stoitzner P, McLellan AD. NK cells are required for dendritic cell-based immunotherapy at the time of tumor challenge. Journal of Immunology. 2014;192:2514-2521. DOI: 10.4049/jimmunol.1202797
  105. 105. Boudreau JE, Bridle BW, Stephenson KB, Jenkins KM, Brunellière J, Bramson JL, Lichty BD, Wan Y. Recombinant vesicular stomatitis virus transduction of dendritic cells enhances their ability to prime innate and adaptive antitumor immunity. Molecular Therapy. 2009;17:1465-1472. DOI: 10.1038/mt.2009.95
  106. 106. Van Tendeloo VF, Van de Velde A, Van Driessche A, Cools N, Anguille S, Ladell K, Gostick E, Vermeulen K, Pieters K, Nijs G, Stein B, Smits EL, Schroyens WA, Gadisseur AP, Vrelust I, Jorens PG, Goossens H, de Vries IJ, Price DA, Oji Y, Oka Y, Sugiyama H, Berneman ZN. Induction of complete and molecular remissions in acute myeloid leukemia by Wilms’ tumor 1 antigen-targeted dendritic cell vaccination. Proceedings of the National Academy of Sciences. 2010;107:13824-13829. DOI: 10.1073/pnas.1008051107
  107. 107. Vera M, Razquin N, Prieto J, Melero I, Fortes P, González-Aseguinolaza G. Intratumoral injection of dendritic cells transduced by an SV40-based vector expressing Interleukin-15 induces curative immunity mediated by CD8+ T lymphocytes and NK cells. Molecular Therapy. 2005;12:950-959. DOI: 10.1016/j.ymthe.2005.03.030
  108. 108. Yamazaki C, Sugiyama M, Ohta T, Hemmi H, Hamada E, Sasaki I, Fukuda Y, Yano T, Nobuoka M, Hirashima T, Iizuka A, Sato K, Tanaka T, Hoshino K, Kaisho T. Critical roles of a dendritic cell subset expressing a chemokine receptor, XCR1. Journal of Immunology. 2013;190:6071-6082. DOI: 10.4049/jimmunol.1202798

Written By

João Calmeiro, Mylene Carrascal, Célia Gomes, Amílcar Falcão, Maria Teresa Cruz and Bruno Miguel Neves

Submitted: 30 January 2018 Reviewed: 18 May 2018 Published: 05 November 2018