Natural killer (NK) cells are crucial components of the innate immune system and play critical roles in host immunity against viral infections and cancer. NK cells’ activity is controlled by the interaction of a wide range of receptors expressed on their surfaces with cell surface ligands. Opposite signals delivered by inhibitory and activating receptors tightly regulate NK cells’ cytotoxicity. Natural killer cells can discriminate between normal and cancer cells. NK cells are known to directly recognize and kill malignant cells or induce apoptosis. However, tumor cells have the ability to evade those attacks. The main mechanisms involve the lack of expression or downregulation of the expression of major histocompatibility complex (MHC) class I molecules and secretion of soluble NKG2D ligands by tumor cells. Furthermore, tumors harbor a population of cancer stem cells (CSCs), which can drive tumor progression and therapeutical resistance. This chapter highlights the roles of NK cells in tumor immunosurveillance and their applications for cancer immunotherapy. NK cell biology and function as well as the role of their receptor interactions will be described. We will discuss the therapeutic applications of NK cells in cancer and NK cells targeting CSCs as a promising strategy for cancer therapy.
- NK cells
- cancer stem cells
Natural killer (NK) cells constitute a minor subset of lymphocytes that are crucial components of the innate immune system and play critical roles in host immunity against malignant cells and virus-infected cells but also in bacterial, fungal, and parasite immune responses . NK cells represent 10% of the lymphocytes in human peripheral blood, and they comprise the third largest population of lymphocytes following B and T cells.
Natural killer cells have diverse biological functions including killing pathogen-infected cells and cancer cells as well as an immunoregulatory role . Natural killer cells can discriminate between normal cells and cells that do not express adequate amounts of major histocompatibility complex (MHC) class I molecules.
NK cell cytotoxicity is regulated by a balance between activating and inhibitory signals delivered by receptors expressed at the cell surface. These cells are known to directly recognize and kill malignant cells or induce apoptosis. However, tumor cells have the ability to evade immunosurveillance by using multiple mechanisms. Furthermore, tumors harbor a population of cancer stem cells (CSC), which is responsible of tumor progression and therapeutical resistance.
Therapeutic applications of NK cells in cancer and NK cells targeting cancer stem cells (CSCs) represent a promising strategy for cancer immunotherapy.
2. NK cells’ biology and function
NK cells originate from common lymphoid progenitor cells and further differentiate into immature/mature NK cells in bone marrow. They are then distributed in peripheral lymphoid and nonlymphoid organs and tissues [3–5], including bone marrow, spleen, peripheral blood, placenta, lung, liver, uterus , and peritoneal cavity while limited numbers are localized in lymph nodes . Human NK cell turnover in blood is around 2 weeks .
NK cells were originally described as large granular lymphocytes with natural cytotoxicity against tumor cells. NK cells were later recognized as a separate lymphocyte lineage, with both cytotoxicity and immunoregulatory role, as they are involved in the production of cytokines . More recently, data revealed that activated NK cells may also influence the outcome of helminth infections. CD4-NK cells increasing early following nematode infection with
NK cells mediate two predominant pathways of cell death. The first pathway, a granule exocytosis pathway , involves the release of cytotoxic granule, perforin (a membrane-disrupting protein), and granzymes (a family of structurally related serine proteases) responsible for NK cell-mediated killing by inducing apoptosis of the target cell [25–27]. In the second pathway, a caspase-dependent apoptosis involves the association of death receptors such as first apoptosis signal (Fas) cell surface death receptor and tumor-necrosis-factor–related apoptosis inducing ligand receptor (TRAILR) on target cells with their corresponding ligands, members of the tumor necrosis factor (TNF) family of cytokines, expressed by NK cells, and regulated by IFN-γ, such as FASL, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), resulting in caspase-dependent target cell apoptosis [28–32]. Antibody-dependent cellular cytotoxicity (ADCC) can also be a mechanism of killing of tumor cells by NK cells by triggering the NK CD16 receptor (FcγRIII), which binds to the IgG and antibody-coated targets .
Natural killer cells can discriminate between normal cells and those that do not express adequate amounts of MHC class I molecules. They were originally defined by their ability to spontaneously eliminate cells lacking expression of MHC class I molecules. NK cells express receptors that bind to MHC class I molecules including the killer cell immunoglobulin-like receptors (KIRs) that play major roles in regulating the activation thresholds of NK cells in humans .
3. NK cell cytotoxicity
NK cell cytotoxicity is tightly regulated by a balance between activating and inhibitory signals  delivered by a multitude of receptors expressed at the cell surface  (Figure 1). The inhibitory NK cell receptors interact with MHC class I molecules expressed on almost all nucleated cells, preventing NK cell activation against healthy cells (Figure 2a). NK cell activation is blocked through engagement of their KIR receptors . This explains self-tolerance and prevention of host cell killing. NK cells can discriminate between normal host cells and infected or abnormal cells by recognition of MHC class I molecules. It was earlier discovered that NK cells are activated when they encounter cells that lack self-MHC class I molecule. For example, under stress conditions, such as cellular transformation, cells downregulate MHC-I expression causing NK cells to lose inhibitory signaling and be activated in a process called “missing-self recognition” . This model is based on the fact that NK cell activity is normally controlled by self-MHC molecules that interact with a large repertoire of inhibitory NK receptors. In this condition, activation receptors are no longer suppressed and they induce potent stimulatory signals, resulting in NK cell activation including cytokine production and granule release leading to cytotoxicity [39, 40]. Abnormal cells can also upregulate the expression of ligands to activate receptors on the NK cells that can overcome the inhibitory signals.
3.1. Activating NK cell receptors
NK cells require external signals to begin the process of cell activation, which usually occurs via triggering receptors. A number of receptors have been identified that allow NK cells to become activated. The major activating receptors expressed on human NK cells include the natural cytotoxicity receptors (NCRs: NKp30, NKp44, NKp46), the immunoglobulin gamma Fc-region receptor III (FcγRIII/CD16), activating forms of killer cell Ig-like receptors (KIR: KIR2DS and KIR3DS), NKG2D, C-type lectin receptors (CD94/NKG2C, NKG2E/H, and NKG2F), NKp80, and 2B4 . NKG2D and NCRs are particularly important receptors for triggering NK cell responses toward tumor cells .
A new family of receptors that recognize nectin and nectin-like molecules has recently emerged as a critical regulator of NK cell functions — DNAX accessory molecule 1 (DNAM-1, CD226) is an adhesion molecule that controls NK cell cytotoxicity and interferon-γ production against a wide range of cancer and infected cells .
The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans . Activating KIR receptor recognizes classical MHC-I molecules , whereas NKG2D recognizes the nonclassical MHC-I molecules, MICA/MICB, retinoic acid early transcript 1E protein (RAET1E), RAET1G, RAET1H, RAET1I, RAET1L, and RAET1N (also known as ULBP1–ULBP6) [46, 47]. These ligands are not present on the cell surface of most normal cells, but are upregulated at the cell surface after cellular stress, on rapidly proliferating cells, infected cells, transformed cells, and tumor cells , further increasing the NK cell activity . CD16 binds the Fc portion of IgG antibodies to initiate antibody-dependent cellular cytotoxicity (ADCC) and provides NK cells with the ability to recognize and kill target cells coated with antibodies . DNAM-1 ligands CD112 and CD155 have been described in different pathological conditions, and recent evidence indicates that their expression is regulated by cellular stress.
All of these activating receptors promote cytotoxicity and cytokine production responses through stimulating intracellular protein tyrosine kinase cascades.
3.2. Inhibitory NK cell receptors
Inhibitory receptors are able to prevent the activation of NK cells and have been thought of as fail-safe mechanisms to prevent attack on normal cells and tissues. In general, these receptors express one or more immunoreceptor tyrosine-based inhibition motifs (ITIM), and they recruit SH2-containing phosphatase-1 (SHP1), SH2-containing phosphatase-2 (SHP2), and/or SH2-containing inositol phosphatase (SHIP) proteins upon binding to their ligands . These phosphatases prevent the activation of cellular signaling cascades by inhibiting phosphorylation of proteins.
The inhibitory receptors encompass two distinct classes: the monomeric type I glycoprotein of the immunoglobulin superfamilies KIR2DL and KIR3DL , leukocyte immunoglobulin-like receptors (ILT2), and the hetero-dimeric C-type lectin-like receptor (CTLR) called CD94/NKG2A (natural killer group protein 2 family member A) [52, 53].
4. NK cells in tumor immunosurveillance and cancer
NK cells are innate cellular components that regulate adaptive immune responses in the immune surveillance of cancer. Primary immunodeficiencies affecting NK cells were associated with higher rates of malignancy and a higher risk of developing various types of cancer [54, 55]. NK cells have been shown to control the growth and metastasis of transplantable tumors in numerous mouse models by antibody depletion of NK cells .
NK cells can eliminate tumors that downregulate expression of MHC class I (Figure 2b), possibly in response to selective pressure exerted by CD8+ T cells. Furthermore, NK cells can kill tumor cells that retain full expression of MHC class I if they have upregulated ligands that engage activating NK cell receptors, thus overriding the inhibitory signals (Figure 2c).
For example, NKG2D ligand expression on tumor cells induces NK cell activation and is sufficient to overcome inhibitory signals delivered by MHC class I receptors, thereby enabling NK cells to eliminate tumors expressing normal levels of MHC class I [48, 57]. Mice deficient of NKG2D (
However, tumor cells are able to evade immunosurveillance by using multiple mechanisms. Tumor cells can secrete inhibitory cytokines such as transforming growth factor-β (TGFβ) that suppresses the activity of NK cells. Furthermore, tumor cells can express inhibitory receptor-specific ligands such as glucocorticoid-induced TNFR-related protein (GITR) that can downmodulate activating receptors NKG2D on NK cells. To escape to NK cell immunosurveillance, tumor cells can also secrete immunomodulatory molecules such as prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), adenosine, TGFβ, and interleukin-10 (IL-10). Tumor cells can proteolytically shed NKG2D ligands (NKG2DLs) leading to a decreased amount of NKG2DL and to the production of soluble ligands that downmodulate NKG2D receptor on NK cells [59, 60]. Finally, secretion of immunosuppressive molecules or expression of NKG2DLs by cells of the tumor microenvironment can downmodulate NKG2D receptor on NK cells.
Soluble NKG2DLs have been detected at high levels in the serum of cancer patients  and might be used as a diagnostic marker . Tumor cells can escape immunosurveillance by the secretion of soluble factors such as lactate dehydrogenase, leading to NKG2DLs expression on healthy host myeloid cells . NKG2D Downregulation could be the result of its chronic exposure to NKG2D ligand on tumor cells . Recent work in a mouse model suggests that a shed NKG2D ligand, MULT1, stabilizes expression of NKG2D on NK cells and increase their antitumor activity . Controlling NKG2DL expression level on tumors provides an attractive therapeutic strategy for immunotherapy.
In patients and animal models, impaired NK cells or NK cell deficiency have been associated not only with recurring viral infections, but also with an increased incidence of various types of cancer . Tumor cells often acquire the ability to escape NK cell-mediated immune surveillance. In fact, during tumor development and progression, many malignant cells acquire the ability either to evade from NK cell recognition or to impair NK cell function.
Cells undergoing malignant transformation often downregulate their expression of MHC class I molecules, and the absence of inhibitory signaling on NK cells permits their function. A defective immunity has been well established in different types of cancer. The imbalance of immune status is inclined to immunosuppression in cancer patients, which results in tumor immune evasion. Such immunosuppression is characterized by a decrease in NK cell numbers in peripheral blood and a decreased tumor infiltrate as compared to normal tissues. Moreover, in many types of cancer, a defective expression of activating receptors and overexpression of inhibitory receptors is observed .
The role of NK cells against parasites that may promote or impede carcinogens is poorly understood. Chronic inflammation is a key feature in carcinogenesis associated with helminth infections. For example,
5. NK cell in cancer immunotherapy
Cancer immunotherapy is the targeted therapy designed to induce antitumor response against malignancies by harnessing the power of the immune system . The ability to recognize and lyse transformed cells without prior immunization, the ease of isolation and expansion
5.1. Adoptive NK cell transfer therapy
Adoptive NK cell transfer therapy is a strategy aimed at enhancing the biological function of the immune system by means of autologous or allogeneic NK cells. NK cells for adoptive NK cell transfer therapy (autologous or allogeneic) are usually obtained from the peripheral blood of the patient or from a donor. They can also be derived from the bone marrow, umbilical-cord blood, human embryonic stem cells, or induced pluripotent stem cells and are now considered as alternative sources of therapeutic NK cells .
Various approaches exist for the therapy with the adoptive transfer of NK cells. In autologous transfer, NK cells from the patient are activated and expanded in vitro in the presence of cytokines. IL-2 has been used for this purpose, but recently, the combination of IL-12, IL-15, and IL-18 might generate NK cells that are more functional and have memory properties. The expanded and activated NK cells are then transferred back into the patient. To sustain the expansion and function of the infused NK cells, patient receives IL2 cytokine administration. Although autologous NK cells might recognize activating signals such as stress molecules on cancer cells, their anti-tumor activity is limited by the inhibitory signal transmitted by self-HLA molecules.
In allogenic transfer, NK cells can be obtained from HLA-matched or haploidentical (partially matched) donors. The best responses are obtained when haploidentical donors do not express KIRs that recognize the patient’s HLA molecules, because donor NK cells do not receive an inhibitory signal from the patient’s cancer cells. NK cells are expanded through processes similar to those used for autologous transfer except that T cells should be removed.
5.1.1. CAR-engineered NK cells
NK cells can be transduced with activating chimeric antigen receptors (CARs) that specifically bind to antigens overexpressed by tumor cells. CARs are designed by the fusion of an antigen binding with a hinge region, a transmembrane domain and one or more stimulatory molecules. CARs can be engineered in autologous or allogeneic NK cells or in NK cell lines such as NK-92. Each CAR has the CD3ζ chain (or sometimes the FcRγ chain) as its main signaling domain. To increase persistence and superior functionality, co-stimulatory domains, usually from CD28 or CD137, can be added to the CAR construct. CARs from the first generation have no stimulatory domain, whereas CARs from the second generation and third generation have one co-stimulatory domain or two co-stimulatory domains, respectively. CAR engineering endows NK cells with antigen specificity. The binding of a CAR to the tumor antigen delivers a potent activating signal that triggers NK cell cytotoxicity, which results in the elimination of cancer cells. Several recent studies have documented a success using NK cells engineered to express activating chimeric antigen receptors (CARs) specific to tumor antigens . Many B-cell acute and chronic leukemia can escape killing by natural killer cells. The introduction of chimeric antigen receptors (CAR) into T cells or NK cells could potentially overcome this resistance . NK-92 leukemia cell lines were transduced to express CARs specific for CD19  and CD20  expressed on B cell malignancies and also for disialoganglioside GD2, a glycolipid expressed on neuroblastoma and various other cancer types .
In glioblastoma, the most aggressive primary brain malignancy, intracranial administration of NK-92-EGFR-CAR cells represents a promising therapy . In human multiple myeloma (MM), CS1-specific (a surface protein highly expressed on MM cells) chimeric antigen receptor (CAR)-engineered natural killer cells  enhance responses to tumor cells in vitro and suppressed tumor growth when tested in vivo in xenograft models [65, 78, 80]. Autologous or allogeneic transplantation of CS1-specific CAR NK cells may be a promising strategy to treat multiple myeloma.
5.2. Cytokine-induced NK cell activation
To promote NK cell expansion, the use of IL-2 has demonstrated the effectiveness on NK cell activation and anti-tumor responses . It was reported that NK cells from lung cancer patients could regain the cytotoxicity against targets after activation by IL-2 . However, NK cells activation using high-dose IL-2 has some side effects because of severe capillary leaky syndrome. To improve the therapeutic efficacy and safety, a different strategy combining IL-2 with other NK cell activators was used. Hellstrand et al.  administered IL-2 together with histamine to 22 acute myeloid leukemia (AML) patients and showed a good clinical outcome. IL-2 diphtheria toxin (IL2DT), a recombinant cytotoxic fusion protein has been used in order to increase the depletion of regulatory T cells (Treg) and therefore improving in vivo donor NK cell expansion and remission induction .
5.3. NK cells targeting cancer stem cells
Tumor harbors a population of cancer cells with “stem-cell” like properties including self-renewal and the ability to produce differentiated progeny . These cells termed cancer stem cells (CSCs) can drive tumor progression and therapeutic resistance to standard cancer therapy. In fact, cancer stem cells have been proposed as an important mechanism of tumor initiation and/or repopulation after tumor debulking by chemotherapy and/or by radiotherapy.
In addition, CSCs have been associated with tumor relapse and metastasis, even in cases of apparent complete response to systemic therapy . Then, targeting CSCs is a promising strategy for cancer therapy. Natural killer cells have the ability to reject allogeneic hematopoietic stem cells, and there are increasing data demonstrating that NK cells can selectively identify and lyse CSCs. Tallerico et al. , for example, demonstrated that metastatic colorectal cancer, which contains a high proportion of CSCs, showed increased susceptibility to NK cytotoxicity. Similarly, Castriconi et al.  reported that glioblastoma-derived CSCs were susceptible to NK cell cytotoxicity. Human cancer cells with stem cell-like phenotype exhibit enhanced sensitivity to the cytotoxicity of IL-2 and IL-15 activated natural killer cells . IL-2- and IL-15-activated NK cells were found to be cytotoxic against human breast cancer stem cells and CD 133+ melanoma CSCs . Recently, Ames et al.  showed that NK cells kill CSCs from different kinds of tumors, through the interaction of the NKG2D activating receptor with its ligand (MICA/B).
NK cells have a crucial role in immunosurveillance against tumor development. However, when both the innate and adaptive immune systems fail and tumors develop, NK cells and their receptors can still be targeted in many therapeutic approaches. NK cells are more effective in treating hematologic malignancies than in treating solid tumors. This might result from inefficient homing of NK cells to the site of tumor. Therefore, NK cell-based immunotherapy can be successfully exploited in the hematopoietic stem cell transplantation for the treatment of hematological malignancies, but efforts have to be made to improve the homing and in vivo persistence of NK cells. Targeting CSCs with NK cell-based immunotherapy represents an attractive strategy for cancer therapy.
NK cells clearly have a role in future immunotherapies of the treatment of cancer and should continue to be evaluated in clinical trials.
Bouzani M, Ok M, McCormick A, Ebel F, Kurzai O, Morton CO, Einsele H, Loeffler J. Human NK cells display important antifungal activity against Aspergillus fumigatus, which is directly mediated by IFN-gamma release. Journal of Immunology. 2011; 187(3):1369-1376
Glas R, Franksson L, Une C, Eloranta ML, Ohlén C, Orn A, et al. Recruitment and activation of natural killer (NK) cells in vivodetermined by the target cell phenotype. An adaptive component of NK cell-mediated responses. The Journal of Experimental Medicine. 2000; 191(1):129-138
Farag SS, Caligiuri MA. Human natural killer cell development and biology. Blood Reviews. 2006; 20:123-137
Freud AG, Caligiuri MA. Human natural killer cell development. Immunological Reviews. 2006; 214:56-72
Vacca P, Vitale C, Montaldo E, Conte R, Cantoni C, Fulcheri E, Darretta V, Moretta L, Mingari MC. CD34+ hematopoietic precursors are present in human decidua and differentiate into natural killer cells upon interaction with stromal cells. Proceedings of the National Academy of Sciences of the United States of America. 2011; 108:2402-2407
Acar N, Ustunel I, Demir R. Uterine natural killer (uNK) cells and their missions during pregnancy: A review. Acta Histochemica. 2011; 113(2):82-91
Fehniger TA, Cooper MA, Nuovo GJ, Cella M, Facchetti F, Colonna M, Caligiuri MA. CD56 bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: A potential new link between adaptive and innate immunity. Blood. 2003; 101(8):3052-3057
Zhang Y et al. In vivo kinetics of human natural killer cells: The effects of ageing and acute and chronic viral infection. Immunology. 2007; 121:258-265
Campbell KS, Hasegawa J. Natural killer cell biology: An update and future directions. The Journal of Allergy and Clinical Immunology. 2013; 132(3):536-544
Balmer P, Devaney ENKT. Cells are a source of early interleukin-4 following infection with third-stage larvae of the filarial nematode Brugia pahangi. Infection and Immunity. 2002; 70:2215-2219
Faveeuw C, Mallevaey T, Trottein F. Role of natural killer T lymphocytes during helminthic infection. Parasite. 2008; 15(3):384-888
Allen JE, Maizels RM. Diversity and dialogue in immunity to helminths. Nature Reviews. Immunology. 2011; 11(6):375-388
McDermott JR, Humphreys NE, Forman SP, Donaldson DD, Grencis RK. Intraepithelial NK cell-derived IL-13 induces intestinal pathology associated with nematode infection. Journal of Immunology. 2005; 175:3207-3213
Hepworth MR, Grencis RK. Disruption of Th2 immunity results in a gender-specific expansion of IL-13 producing accessory NK cells during helminth infection. Journal of Immunology. 2009; 183(6):3906-3914
Caligiuri MA. Human natural killer cells. Blood. 2008; 112(3):461-469
Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nature Immunology. 2008; 9(5):503-510
De Maria A, Bozzano F, Cantoni C, Moretta L. Revisiting human natural killer cell subset function revealed cytolytic CD56(dim)CD16+ NK cells as rapid producers of abundant IFN-gamma on activation. Proceedings of the National Academy of Sciences of the United States of America. 2011; 108:728-732
Fauriat C, Long EO, Ljunggren HG, Bryceson YT. Regulation of human NK-cell cytokine and chemokine production by target cell recognition. Blood. 2010; 115:2167-2176
Anfossi N et al. Human NK cell education by inhibitory receptors for MHC class I. Immunity. 2006; 25:331-342
Ferlazzo G, Munz C. NK cell compartments and their activation by dendritic cells. Journal of Immunology. 2004; 172:1333-1339
Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killercell subsets. Trends in Immunology. 2001; 22:633-640
Hsieh GC, Loukas A, Wahl AM, Bhatia M, Wang Y, Williamson AL, Kehn KW, Maruyama H, Hotez PJ, Leitenberg D, Bethony J, Constant SL. A secreted protein from the human hookworm Necator americanusbinds selectively to NK cells and induces IFN-gamma production. Journal of Immunology. 2004; 173(4):2699-2704
Gregoire C, Chasson L, Luci C, Tomasello E, Geissmann F, Vivier E, Walzer T. The trafficking of natural killer cells. Immunological Reviews. 2007; 220:169-182
Krzewski K, Coligan JE. Human NK cell lytic granules and regulation of their exocytosis. Natural Killer Cell Biology. 2012; 3:335
Kagi D, Ledermann B, Burki K, Seiler P, Odermatt B, Olsen KJ, Podack ER, Zinkernagel RM, Hengartner H. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature. 1994; 369:31-37
Trapani JA, Davis J, Sutton VR, Smyth MJ. Proapoptotic functions of cytotoxic lymphocyte granule constituents in vitro and in vivo. Current Opinion in Immunology. 2000; 12:323-329
Voskoboinik I, Whisstock JC, Trapani JA. Perforin and granzymes: Function, dysfunction and human pathology. Nature Reviews. Immunology. 2015; 15:388-400
Nagata S. Apoptosis by death factor. Cell. 1997; 88:355-365
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
Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S, Iwakura Y, Yagita H, Okumura K. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nature Medicine. 2001; 7:94-100
Cretney E, Takeda K, Yagita H, Glaccum M, Peschon JJ, Smyth MJ. Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. Journal of Immunology. 2002; 168:1356-1361
Smyth MJ et al. Activation of NK cell cytotoxicity. Molecular Immunology. 2005; 42:501-510
Hooijberg E, Sein JJ, van den Berk PC, Hekman A. Characterization of a series of isotype switch variants of a new CD20 monoclonal antibody. Hybridoma 1996; 15:23-31
Campbell KS, Purdy AK. Structure/function of human killer cell immunoglobulin-like receptors: Lessons from polymorphisms, evolution, crystal structures and mutations. Immunology. 2011; 132:315-325
Morvan MG, Lanier LLNK. Cells and cancer: You can teach innate cells new tricks. Nature Reviews. Cancer. 2016; 16(1):7-19
Del Zotto G, Marcenaro E, Vacca P, Sivori S, Pende D, Della Chiesa M, Moretta F, Ingegnere T, Mingari MC, Moretta A, Moretta L. Markers and function of human NK cells in normal and pathological conditions. Cytometry. Part B, Clinical Cytometry. 2017; 92(2):100-114
Lanier LL. Up on the tightrope: Natural killer cell activation and inhibition. Nature Immunology. 2008; 9:495-502
Kärre K, Ljunggren HG, Piontek G, Kiessling R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature. 1986; 319:675-678
Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science. 1999; 285(5428):727-739
Cassidy SA, Cheent KS, Khakoo SI. Effects of peptide on NK cell-mediated MHC I recognition. Frontiers in Immunology. 2014; 5:133
MacFarlane IVAW, Campbell KS. Signal transduction in natural killer cells. Current Topics in Microbiology and Immunology. 2006; 298:23-57
Mentlik James A, Cohen AD, Campbell KS. Combination immune therapies to enhance anti-tumor responses by NK cells. Frontiers in Immunology. 2013; 4:481
De Andrade LF, Smyth MJ, Martinet L. DNAM-1 control of natural killer cells functions through nectin and nectin-like proteins. Immunology and Cell Biology. 2014; 92(3):237-244
Brandt CS, Baratin M, Yi EC, Kennedy J, Gao Z, Fox B, et al. The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. The Journal of Experimental Medicine. 2009; 206:1495-1503
Purdy AK, Campbell KS. Natural killer cells and cancer: Regulation by the killer cell Ig-like receptors (KIR). Cancer Biology & Therapy. 2009; 8(23):2211-2220
Steinle A, Li P, Morris DL, Groh V, Lanier LL, Strong RK, et al. Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family. Immunogenetics. 2001; 53:279-287
Lanier LL. NKG2D receptor and its ligands in host defense. Cancer Immunology Research. 2015; 3:575-582
Raulet DH, Gasser S, Gowen BG, Deng W, Jung H. Regulation of ligands for the NKG2D activating receptor. Annual Review of Immunology. 2013; 31:413-441
Terszowski G, Passweg JR, Stern M. Natural killer cell immunity after transplantation. Swiss Medical Weekly. 2012; 142:w13700
Ahmad A, Menezes J. Antibody-dependent cellular cytotoxicity in HIV infections. The FASEB Journal. 1996; 10:258-266
Lanier LL. NK cell recognition. Annual Review of Immunology. 2005; 23:225-274
Lee N, Llano M, Carretero M, Ishitani A, Navarro F, Lopez-Botet M, Geraghty DE. HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proceedings of the National Academy of Sciences of the USA. 1998; 95:5199-5204 malhotra/shanker2011
Malhotra A, Shanker A. NK cells: Immune cross-talk and therapeutic implications. Immunotherapy. 2011; 3(10):1143-1166
Imai K, Matsuyama S, Miyake S, Suga K, Nakachi K. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: An 11-year follow-up study of a general population. Lancet. 2000; 356:1795-1799
Orange JS. Natural killer cell deficiency. The Journal of Allergy and Clinical Immunology. 2013; 132:515-525
Smyth MJ, Hayakawa Y, Takeda K, Yagita H. New aspects of natural-killer-cell surveillance and therapy of cancer. Nature Reviews. Cancer. 2002; 2(11):850-861
Cerwenka A, Baro JL, Lanier LL. Ectopic expression of retinoic acid early inducible-1 gene ( RAE- 1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proceedings of the National Academy of Sciences of the United States of America. 2001; 98:11521-11526
Guerra N et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity. 2008; 28:571-580
Groh V, Wu J, Yee C, Spies T. Tumor-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature. 2002; 419:734-738
Kaiser BK et al. Disulphide-isomerase-enabled shedding of tumor-associated NKG2D ligands. Nature. 2007; 447:482-486
Salih HR, Holdenrieder S, Steinle A. Soluble NKG2D ligands: Prevalence, release, and functional impact. Frontiers in Bioscience. 2008;(13):3448-3456
Holdenrieder S et al. Soluble MICA in malignant diseases. International Journal of Cancer. 2006; 118:684-687
Crane CA et al. Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients. Proceedings of the National Academy of Sciences of the United States of America. 2014; 111:12823-12828
Champsaur M, Lanier LL. Effect of NKG2D ligand expression on host immune responses. Immunological Reviews. 2010; 235:267-285
Deng W et al. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection. Science. 2015; 348:136-139
Guillerey C, Huntington ND, MJ1 S. Targeting natural killer cells in cancer immunotherapy. Nature Immunology. 2016; 17(9):1025-1036
Tanaka T, Hirata T, Parrott G, Higashiarakawa M, Kinjo T, Kinjo T, Hokama A, Fujita J. Relationship among Strongyloides stercoralisinfection, human T-cell lymphotropic virus type 1 infection, and cancer: A 24-year cohort inpatient study in Okinawa, Japan. The American Journal of Tropical Medicine and Hygiene. 2016; 94(2):365-370
Tomaino C, Catalano C, Tiba M, Aron J, Su. A first case report of colorectal cancer associated with chronic Strongyloides stercoraliscolitis and the complex management decisions that follow. Gastroenterology. 2015; 148(4):Suppl.1):S575
Satoh M, Toma H, Sugahara K, Etoh K, Shiroma Y, Kiyuna S, Takara M, Matsuoka M, Yamaguchi K, Nakada K, Fujita K, Kojima S, Hori E, Tanaka Y, Kamihira S, Sato Y, Watanabe T. Involvement of IL-2/IL-2R system activation by parasite antigen in polyclonal expansion of CD4(+)25(+) HTLV-1-infected T-cells in human carriers of both HTLV-1 and S. stercoralis. Oncogene. 2002; 21(16):2466-2475
Myers B, Speight EL, Huissoon AP, Davies JM. Natural killer-cell lymphocytosis and strongyloides infection. Clinical and Laboratory Haematology. 2000; 22(4):237-238
Cheng M, Chen Y, Xiao W, Sun R, Tian Z. NK cell-based immunotherapy for malignant diseases. Cellular & Molecular Immunology. 2013; 10:230-252
Becker PS et al. Selection and expansion of natural killer cells for NK cell-based immunotherapy. Cancer Immunology, Immunotherapy. 2016; 65:477-484
Hermanson DL, Kaufman DS. Utilizing chimeric antigen receptors to direct natural killer cell activity. Frontiers in Immunology. 2015; 6:195
Romanski A, Uherek C, Bug G, Seifried E, Klingemann H, Wels WS, Ottmann OGT. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. Journal of Cellular and Molecular Medicine. 2016; 20(7):1287-1294
Boissel L, Betancu M, Wels WS, Tuncer H, Klingemann H. Transfection with mRNA for CD19 specific chimeric antigen receptor restores NK cell mediated killing of CLL cells. Leukemia Research. 2009; 33:1255-1259
Müller T et al. Expression of a CD20-specific chimeric antigen receptor enhances cytotoxic activity of NK cells and overcomes NK-resistance of lymphoma and leukemia cells. Cancer Immunology, Immunotherapy. 2007; 57:411-423
Ahmed M, Hu J, Cheung NK. Structure based refinement of a humanized monoclonal antibody that targets tumor antigen disialoganglioside GD2. Frontiers in Immunology. 2014; 5:372
Han J et al. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. Scientific Reports. 2015; 5:11483
Jiang H et al. Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells. Molecular Oncology. 2014; 8:297-310
Müller N, Michen S, Tietze S, Töpfer K, Schulte A, Lamszus K, Schmitz M, Schackert G, Pastan I, Temme A. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1α-secreting Glioblastoma. Journal of Immunotherapy. 2015; 38(5):197-210
Becknell B, Caligiuri MA. Interleukin-2, interleukin-15, and their roles in human natural killer cells. Advances in Immunology. 2005; 86:209-239
Robinson BW, Morstyn G. Natural killer (NK)-resistant human lung cancer cells are lysed by recombinant interleukin-2-activated NK cells. Cellular Immunology. 1987; 106:215-222
Hellstrand K, Mellqvist UH, Wallhult E, Carneskog J, Kimby E, Celsing F, Brune M. Histamine and interleukin-2 in acute myelogenous leukemia. Leukemia & Lymphoma. 1997; 27:429-438
Bachanova V, Cooley S, Defor TE, Verneris MR, Zhang B, McKenna DH, Curtsinger J, Panoskaltsis-Mortari A, Lewis D, Hippen K, McGlave P, Weisdorf DJ, Blazar BR, Miller JS. Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. Blood. 2014; 123:3855-3863
Clarke MF. Oncogenes, self-renewal and cancer. Pathologie Biologie (Paris). 2006; 54(2):109-111
Visvader JE, Lindeman GJ. Cancer stem cells: Current status and evolving complexities. Cell Stem Cell. 2012; 10:717-728
Tallerico R, Todaro M, Di Franco S, et al. Human NK cells selective targeting of colon cancer-initiating cells: A role for natural cytotoxicity receptors and MHC class I molecules. Journal of Immunology. 2013; 190(5):2381-2390
Castriconi R, Daga A, Dondero A, et al. NK cells recognize and kill human glioblastoma cells with stem cell-like properties. Journal of Immunology. 2009; 182(6):3530-3519
Yin T, Wang G, He S, Liu Q, Sun J, Wang Y. Human cancer cells with stem cell-like phenotype exhibit enhanced sensitivity to the cytotoxicity of IL-2 and IL-15 activated natural killer cells. Cellular Immunology. 2016; 300:41-45
Pietra G, Manzini C, Vitale M, Balsamo M, Ognio E, Boitano M, Queirolo P, Moretta L, Mingari MC. Natural killer cells kill human melanoma cells with characteristics of cancer stem cells. International Immunology. 2009; 21(7):793-801
Ames E, Canter RJ, Grossenbacher SK, Mac S, Chen M, Smith RC, Hagino T, Perez-Cunningham J, Sckisel GD, Urayama S, Monjazeb AM, Fragoso RC, Sayers TJ, Murphy WJ. NK cells preferentially target tumor cells with a cancer stem cell phenotype. Journal of Immunology. 2015; 195(8):4010-4019