Introduction
Natural Killer cells (NK) cells are unique in having the quality of recognizing cells that are abnormally stressed, lacking Major Histocompatibility Complex (MHCs) and without antibodies. The term ‘natural killer’ is relevant in the sense that they do not require prior activation for killing cells lacking MHC class I [1]. This property of NK cells make them efficient in detecting and destroying infected or abnormal cells lacking MHCs and which would otherwise escape detection by immune cells like T lymphocytes [2]. Critical to the innate immune system NK cells are cytotoxic lymphocytes that play a role analogous to cytotoxic T cells in the vertebrate’s adaptive immune response [3]. Typically virally infected cells and tumour cells are susceptible to NK cells. These are large granular cells derived from lymphoid progenitor cells generating T and B lymphocytes. Their maturation and differentiation takes place in bone marrow, lymph nodes, spleen, tonsils and thymus from where they directly join the circulation [4-6].
NK cells lack antigen specific cell surface receptors and are capable of immediate reaction without prior antigen exposure [1]. Recently, NK cells have been recognized to play an important role in tumour immunosurveillance i.e., causing direct death of tumour cells without the presence of surface adhesion molecules or antigenic peptides [7-9]. Detection of tumour cells leads to activation of NK cells following cytokines production and release [9].
Natural Killer Cell Receptors, Their Structure And Functions
NK cells are different from NKT cells based on their origin, infact NKT cells promote the activity of NK cells by promoting the secretion of IFNγ [10]. Unlike NKT cells, the NK cells do not express- T-Cell Antigen Receptors (TCRs), CD3 surface marker or surface B cell receptors. They express surface markers CD16 and CD56 on their surfaces in human beings and the NK cells are usually defined as CD3- CD56+ (5 to 20%) lymphocytes which are primarily divided into two groups namely CD56dim CD16+ and CD56bright CD16 [10,11]. The CD56dim variety has high cytotoxic potential, predominate at the site of inflammation (>90%) and expresses on its surface abundant MHC class I specific inhibitory receptors unlike the CD56bright group of cells which are present predominantly in the lymph nodes, concerned mainly with cytokines secretion and show little toxicity. They are better known as precursors of CD 56dim sub-group [11]. Functional modulation of the NK cells happens through a very well-regulated balance of its activating and inhibitory receptors. Research on NK cells initiated in the mid-1990s, led to cloning and identification of various families of NK cell receptors structural determination of NK cell surface receptors with ligand complexes thereby increasing our understanding of the role of these cells in innate immune response. There are two types of NK cell surface receptors, the inhibitory and activating receptors based on their functions [12]. Also structurally, they can be immunoglobulin like receptor superfamily or the C-type Lectin Like Receptor superfamily (CTLR) [13,14]. The ligands are members of the MHC class-I complex or their homologs [14]. The inhibitory receptors, recognize MHC-I with self-peptide on healthy host cells and provide protection while the activating receptors make facile killing of virally infected and tumour cells through specific ligand recognition system [15].
Inhibitory Receptors
Belonging to multigene family, Ig-like extracellular domain receptors, are killer cell receptors structurally resembling immunoglobulins. They are present in nonhuman primates, are the main receptor for both classical MHC class I and nonclassical Mamu-G (HLA-G). Inhibitory and dominant in nature, few Killer Inhibitory Receptors (KIRs) are specific to some HLA subtypes. Regular cell killing is inhibited by NK cells because they express MHC class I and these are recognized by KIRs. Leucocyte Inhibitory Receptors (LIR) are the members of the Ig receptor family discovered recently. Ly49 are other homodimeric receptors which are both inhibitory and activating in nature [14-16].
Activating Receptors
Natural Cytotoxic Receptors (NCR) on being stimulated cause NK cell mediated killing and release of INFγ. Ly49 (homodimers) and CD94:- NKG2 (heterodimers) both belong to CTLR. Ly49 are the receptors for classical polymorphic MHC I molecules while CD94:-NKG2 identifies nonclassical and nonpolymorphic MHC I molecules such as HLA-E at the cell surface and it also requires the presence of nonamer peptide epitope derived from the signal sequence of classical MHC I molecules. CD16 or Fcy III are other types of receptors which are involved in Antibody Dependent Cell Mediated Cytotoxicity (ADCC) [17-19].
NK cells contain small granules called granzymes like perforin and proteases. During the killing process the NK cells come closer to the altered cell, perforins form small pores in the target cell to create an aqueous channel through which all contents of NK cells including granzymes are transferred to the cell and induce apoptosis [20]. Cell death can also be caused by lysis due to osmotic effects [20,21]. Apoptosis leads to the destruction of viruses inside the cell only while lysis could release virions. Alpha defensin is an antimicrobial substance, secreted by NK cells and can directly kill bacteria. It disrupts and destroys the bacterial cell wall in a similar manner to neutrophils. Opsonized infected cells (with antibodies) can be recognised by FcRIII or CD16 receptors expressed on NK cells leading to their activation. They in turn release cytolytic granules and cause cell death. The ADCC mediated killing of tumour cells can be estimated by transfecting NK-92 with high affinity FcR and comparison with wild type NK-92 which do not express FcRs [22].
Cytokines that are released from virally infected cells also play a prominent role in NK cell activation by signalling the NK cells about the infection. IL-12, IL-15, IL-18, IL-2 and CCL5 are the cytokines involved in NK cell activation [23]. Moreover IFN-γ derived from macrophages also activate NK cells. NK cells control viral infection by secreting INF-γ and TNF-α, role of which are to activate macrophages for phagocytosis and lysis and to cause direct killing by NK cells respectively [24].
Mechanism Of Action Of NK Cells
Scientists have been baffled for years regarding the mechanism by which these cells discriminate between altered and normal cell, as these cells do not possess antigen-specific receptors. NK cells and cytotoxic T-cells work in a complementary manner to produce an immune response directed against viruses and tumour cells. Specific to antigen presented over MHC I, the cytotoxic T-cells recognise antigenic peptides derived from viruses and tumours. In most instances, MHC class I expression is down-regulated by tumours and virus infected cells. The cells are then not recognizable by cytotoxic T-cells i.e., because of which the adaptive immune response fail. However, killing of these cells is then mediated by NK cells. These cells recognize MHC downregulated altered cells which escape Cytotoxic T-Lymphocyte (CTL) killing. The MHC class I molecules are identified by inhibitory receptors of the NK cells while this ligation inhibits the activation of NK cells. The opposite to this is that in cells lacking the MHC I for ligating inhibitory receptors, leads to the activation of NK cells [25,26]. Conversely, it can be said that due to lack of engagement of inhibitory receptors, in addition to other signals results in the activation of cytotoxicity of the NK cells. During viral infection and some forms of malignancy, these altered cells start inducing the expression of MHC class I chain related molecules like MICA, MICB and UL-16 binding proteins. These molecules are recognized by NKG2D receptors and ligand binding can lead to signalling to kill the target cell [27-29].
Immunosurvillance Of Tumour Cells
NK cells perform very important role in fighting tumours as the recognition of these tumour cells is not MHC restricted. Hence, there is no compromise between NK cells and decreased expression exhibited by some altered tumour cells. For the last few years there has been a progressive effort made in the field of NK cell research to decipher the functional aspects of these cells. Also, NK cell based immunotherapy is emerging as a novel and promising approach as a therapeutic agent in treating malignancies. The current knowledge about the NK cells characteristics based on the various ‘missing self’and ‘induced self’, model experiments have led to major advancements in our understanding. Other than T and B cells, the NK cells do not recognize foreign peptide or antigens. These are self-centric in nature meaning that, they can detect changes in self molecules which are displayed on the surface of autologous cells [30]. The MHC class I recognition by inhibitory receptors and inactivation of NK cells clearly explains that virally infected and malignant autologous cells having down-regulation of the MHC I molecules, are only susceptible to attack by NK cells while healthy cells remain unaffected from NK cell toxicity [30]. The ‘missing self’ was not able to explain why human erythrocytes were being spared and why few tumour cells containing abundant quantities of MHC class I molecules, were being killed by NK cells. Ensuing knowledge of various inducible ligands however, have explained that NK cell induction requires the expression of certain inducible ligands for activating NK cell receptors and NK cell response is the sum-total of all the activating and inhibitory signals. However, recognition of the inducible ligand and for validating the activation hypothesis, a thorough investigation and molecular characterization of the ligands is required to better explain NK mediated tumour surveillance phenomenon. Several studies carried out in various animal models have explained the same notion that NK cells are involved in eradication of tumour cells and elimination of these cells leads to more vigorous growth of tumour and its metastasis. Shankaran et al., reported that mice knocked with RAG2 (Recombinase Activating Gene) and STAT1, had a higher rate of development of adenocarcinoma as compared to control and the mice deficient only in RAG2 [31]. Dunn GP et al., and Smyth MJ et al., and Swann JB et al., reported the same finding. Results support that NK cells play a role in tumour surveillance [32-34]. Various cytokines like interleukins i.e., IL-2, IL-12, IL-15, IL-21 and IFN-α/β enhance the activation of NK cells, promote NK cell maturation, surge the cytotoxic activity against tumours and administering these cytokines always heightened the NK cell activity [35,36]. In one of the studies conducted, it was shown that in the initial stages of tumour development, though NK cells arrested and eliminated the tumour but in its dormant stage, these cells were of least importance and adaptive immune system come into play to check the development and chronicity [37].
Several therapeutic interventions including surgery, chemo-therapeutic agents or ionizing radiations, have been adopted as primary strategies to check the tumours. Therapies have been designed to induce potent antitumour response by harnessing the potential of the immune system. But these strategies including cytokines, monoclonal antibodies, vaccines, adoptive cell transfers (T, NK and NKT) and Toll-Like Receptor (TLR) agonists, may not be effective in many of the cases as chances of relapse can occur due to drug resistance or resistance to radiations. The capability of the immune system to eliminate tumour cells till they are fully converted to tumour growth by the phenomenon known as immunosurveillance [38] keeps a dynamic balance in the biological system. The current understanding of NK cell biology, functions etc. has recently led to the development of NK cells as a powerful and potent tool in cancer immunotherapy. NK cell immunotherapy [39] has emerged as a potential alternative through various potential approaches including large-scale production and expansion of the cells for clinical trials and therapeutic purposes, for enhancing the efficacy. Direct killing of the tumour cells is mediated by release of perforins and granzymes leading to cell apoptosis [40], mediated by death receptors and by secreting various effectors like INF-γ [40]. Release of these cytokines is associated with Nitric Oxide (NO) production i.e. the NK cells kill the target cells by NO signalling [41]. Another way of direct killing is through ADCC by expressing CD16 for destroying altered cells. Cytokine like, IL-2, IL-12, IL-18, and IL-15 further stimulate NK cell activity while other induce IFN production. These NK cells also participate indirectly in the killing process. Acting as regulatory cells, NK cells interact with dendritic cells, macrophages, T-cells and endothelial cells through production of various cytokines such as INF-γ, TNF-α, and IL-10 as well as other chemokines and growth factors. By releasing INF-γ, these cells induce CD8+ cytotoxic cells to differentiate into CTLs. They also help in differentiation of CTLs via induction of CD4+ cells. Moreover, in course of killing of tumour cells by NK cells, antigens produced, are taken up by Antigen Presenting Cells (APCs) for induction of adaptive immune response [42].
Tumour cells, during progression adopt several mechanisms to escape from NK cell recognition. In cancerous patients, abnormalities of NK cells have been noticed. These cells also cause generation of defective NK cells via down-regulation of adhesion molecules or production of costimulatory ligands, or by upregulating MHC-I molecules, secreting immunosuppressive factors, resisting fas or perforin mediated apoptosis [43-46]. Sialoglycans affects critical steps in tumour immunology. Different sialoglycants are recognized as ligands to sialic acid binding Ig like lectin-7 (siglec-7), which also known as a pan-NK cell marker, and siglec-9 on human NK cells. Siglec-9 was recently expressed in subset of CD56dim NK cell [47,48]. In various tumour types, vulnerability to NK cell cytotoxicity are affected by the advancement of sialylation status of cancer cells. Since, hypersialylation gives an advantage to tumour cells under pressure from NK immunosurveillance. Through the recruitment of the sialic acid binding immunoglobulin like lectin-7 on the cancer cells, activation of natural killer cells inhibited [49]. Siglec-7 also responsible for inhibiting the function of NK cell when combined with other specific antibodies. It has also been concluded from a study that siglec-7(+) NK cell shows more CD107a degranulation and IFN γ production compared siglec-7(-) NK cells [50]. It is apparent from the direct and indirect killing mechanisms of NK cells that they are very efficient and competent immunotherapeutic agents in the clinical context. In early clinical trials conducted in the 1980s, IL-2 activated NK cells were introduced through subcutaneous injections to treat cancerous patients. Results showed 15-30% positive effects in patients with advanced renal cell carcinoma or melanoma. But IL-2 activated NK cells increase sensitivity to apoptosis when in contact with vascular endothelium with slowing of the migratory rate [51]. Furthermore, other inducers of the NK cells like IL-12, IL-15, IL-21 Flt3-L, SCF, and IL-7 have also been used. Flt3-L leads to the expansion of not only NK cells but also of dendritic cells [52,53]. Other than IL-2 and IL-15, IL-12 mainly enhances the production of INF-γ via NK cells [54]. IL-12 and IL-18 manifest their effects through release of INF-γ [55]. Apoptosis of tumour cells is mediated by INF- γ by, induction of TNF-Related Apoptosis-Inducing Ligand (TRAIL) and FasL- mediated cellular susceptibility to apoptosis [56]. NK cell can also be stimulated by direct engagement of surface TLR3 and TLR9 and some synthetic molecules have been found capable of mimicking the immunostimulatory activity of viral and bacterial products via TLRs [57].
Therapies Based On Nk Cells Targeting Cancer
Prior to adoptive infusion of NK cells, they can be activated through short-term exposure in vitro. To obtain clinically significant amounts of these cells, their long-term expansion is required. Also, in vitro expansion lead to potential phenotypic changes resulting in selective expansion and reduced cytotoxic killing. These concerns can be addressed by improvement in techniques to achieve clinically relevant NK cells with their in vivo anti-tumour efficacy. Several factors influence the clinical efficacy and relevance of the NK cells. These factors include the source of NK cells, type of cytokines used for stimulation, medium of cell culture and conditions, expansion etc. The Peripheral Blood Mononuclear Cells (PBMC), Umbilical Cord Blood (UCB), cell lines, Human Embryonic Stem Cells (HESC), Induced Pluripotent Stem Cells (iPSCs) have been the source of NK cells [58]. PBMCs are processed via apheresis or Ficoll separation under cGMP conditions for NK cell purification [59]. One unique method was adopted by Sukamoto N et al., to generate a large number of NK cells without prior purification of peripheral blood, that is culturing the PBMCs with autologous plasma, IL-2, OK-432 and γ-irradiated autologous T-cells (FN-CH 296 stimulated). On day 21-22 purity level of NK cells reached upto 90.96% [60]. An immunomagnetic depletion approach is another method of purification and enrichment of NK cells involving depletion of other lymphocytes such as T and B-cells, and myloid cells [61]. Nguyen S et al., have reported the beneficial effects of partial T-cells depletion after Haematopoietic Stem Cell (HSC) transplant, thereby suggesting a positive role of T-cells in in vivo stimulation of NK cells activity[62]. Use of feeder cells and cell lines in in vivo expansion of NK cells has also been reported [63]. Further more, direct enrichment of CD56+ cells via immunomagnetic selection is another useful approach [61]. Use of HSC (CD34+) from bone marrow, peripheral blood or UCB through differentiation and expansion of CD34+, can be another potential source to have clinically relevant antitumour NK cells. Recently, a study has shown that frozen CBCD34+ is most promising HSC source for producing NK cells compared to fresh CBCD34+ and frozen PBCD34+ [64]. NK cells derived from UCB are less active exhibiting reduced killing properties, and can be stimulated by ex vivo treatment with IL-2, IL-12, and IL-15 [61]. One of the important sources of NK cells, HESC and iPSC with reduced risk of immune rejection has been reported by Knorr DA et al., [63]. In this procedure, HESCs and iPSCs underwent two stage culture method to differentiate into CD34+ cells via SPIN-EB system [65]. NK cells derived from human embryonic stem cells has the ability to kill the multiple types of tumours in both in vivo and in vitro. NK cells derived from both HESc and IPSC are able to inhibit the HIV-1 NL4-3 infection from CEM-GFP cells [66]. Additionally, a mouse xenograft model based study also have observed that NK cells derived from PB and iPSC having the ability to mediate killing of ovarian cancer cell [67]. In xeno-free and serum-free conditions, cytotoxic NK cells were generated leading to one step forward towards clinical scale production [63].
For off the shelf anticancer therapy, the cell lines derived from NK cells (NK-92, NKL, KYHG-1, and NKG) are potential source. Moreover, genetically modified NK cell lines expressing intracellular IL-2 and cell surface molecules like CD16, NCRs, or Chimeric Antigen Receptors (CARs) have also been used as possible tools for generating activated NK cells [65]. Many genetically modified NK cells have been choosen for clinical trials but all this is still in a nascent stage and several novel potential strategies are under extensive research. To cope up with tumour microenvironment various immunosuppressive therapies are being developed. Many approaches involve triggering of ADCC through monoclonal antibodies, whose antigen binding fragment (Fab) binds to tumour cells and constant region (Fc) binds to CD16 ligand on the NK cell surface [68]. Anti-CD20 (Rituximab), Anti-Her-2 (Trastuzumab), Anti-CD52 (Alemtuzumab) and Anti-EGFR (Cetuximab) are few examples of monoclonal antibodies used for ADCC triggering phenomenon [69].
Conclusion
None of studies are currently done to establish intimate mechanism of NK cells. The multifaceted lytic role of NK cells has been clearly implicated in the tumour cell killing and promising results have been obtained in various experimental models. However, NK cell based immunotherapeutic clinical efficacy in cancer patients is quite moderate and many challenges still need to be overcome.
To increase the activity of NK cells against tumours, various efficacious cytokine combinations with NK cell based immunotherapy have been tried in association of other approaches. For its actual use at the therapeutic level, a good control upon NK cell activity, based on a deep knowledge of their basic physiology at the bench is necessary. Parallel to development of clinically relevant pool of NK cells, there is a need for comparative clinical trials. Various NK cell based products undergoing multicentric clinical trials, will come into the picture in future to assess its efficacy data. Soon, NK cell therapy will probably be one of the most promising tools for the management of human cancer.
[1]. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, Innate or adaptive immunity? The example of natural killer cells Science 2011 331(6013):44-49. [Google Scholar]
[2]. Waldhauer I, Steinle A, NK cells and cancer immunosurveillance Oncogene 2008 27:5932-43. [Google Scholar]
[3]. King PT, Ngui J, Farmer MW, Hutchinson P, Holmes PW, Holdsworth SR, Cytotoxic T lymphocyte and natural killer cell responses to non-typeable Haemophilus influenza Clin Exp Immunol 2008 152(3):542-51. [Google Scholar]
[4]. Luetke-Eversloh M, Killig M, Romagnani C, Signatures of human NK cell development and terminal differentiation Front Immunol 2013 4:499 [Google Scholar]
[5]. Luevano M, Madrigal A, Saudemont A, Generation of natural killer cells from hematopoietic stem cells in vitro for immunotherapy Cell Mol Immunol 2012 9(4):310-20. [Google Scholar]
[6]. Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset Blood 2001 97(10):3146-51. [Google Scholar]
[7]. Lanier LL, A renaissance for the tumour immunosurveillance hypothesis Nat Med 2001 7:1178-80. [Google Scholar]
[8]. Pende D, Cantoni C, Rivera P, Vitale M, Castriconi R, Marcenaro S, Role of NKG2D in tumour cell lysis mediated by human NK cells: cooperation with natural cytotoxicity receptors and capability of recognizing tumours of nonepithelial origin Eur J Immunol 2001 31:1076-86. [Google Scholar]
[9]. Smyth MJ, Hayakawa Y, Takeda K, Yagita H, New aspects of natural-killer-cell surveillance and therapy of cancer Nat Rev Cancer 2002 2:850-61. [Google Scholar]
[10]. Terabe M, Berzofsky JA, The Role of NKT Cells in Tumour Immunity Adv Cancer Res 2008 101:277-348. [Google Scholar]
[11]. Walzer T, Bléry M, Chaix J, Fuseri N, Chasson L, Robbins SH, Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46 Pro Nat Acad Sci USA 2007 104(9):3384-89. [Google Scholar]
[12]. Terunuma H, Deng X, Dewan Z, Fujimoto S, Yamamoto N, Potential role of NK cells in the induction of immune responses: implications for NK cell-based immunotherapy for cancers and viral infections Int Rev Immunol 2008 27(3):93-110. [Google Scholar]
[13]. Yawata M, Yawata N, Abi-Rached L, Variation within the human killer cell immunoglobulin-like receptor (KIR) gene family Immunology 2002 22(5&6):463-82. [Google Scholar]
[14]. Bashirova AA, Martin MP, McVicar DW, Carrington M, The killer immunoglobulin-like receptor gene cluster: tuning the genome for defense Annu Rev Genomics Hum Genet 2006 7:277-300. [Google Scholar]
[15]. Cassidy SA, Cheent KS, Khakoo SI, Effects of peptide on NK cell-mediated MHC I recognition Front Immunol 2014 5:133 [Google Scholar]
[16]. Rajalingam R, Overview of the killer cell immunoglobulin-like receptor system Immunogenetics: Methods and Applications in Clinical Practice 2012 882:391-414. [Google Scholar]
[17]. Paul William E, Fundamental Immunology 2008 6th edPhiladelphiaLippincott Williams & Wilkins:497-503. [Google Scholar]
[18]. Hofer Erhard, Natural killer and leucocyte receptor complexes Munksgaard 2001 :53115 and 123 [Google Scholar]
[19]. Kelley J, Walter L, Trowsdale J, Comparative genomics of natural killer cell receptor gene clusters PLoS Genet 2005 1(2):e27 [Google Scholar]
[20]. Iannello A, Debbeche O, Samarani S, Ahmad A, Antiviral NK cell responses in HIV infection: I. NK cell receptor genes as determinants of HIV resistance and progression to AIDS J Leukoc Biol 2008 84:1-26. [Google Scholar]
[21]. Roitt I, Brostoff J, Male D Immunology Book 2001 6th ed:480 [Google Scholar]
[22]. Zamai L, Ahmad M, Bennett IM, Azzoni L, Alnemri ES, Perussia B, Natural Killer (NK) Cell–mediated Cytotoxicity: Differential Use of TRAIL and Fas Ligand by Immature and Mature Primary Human NK Cells J Exp Med 1998 188(12):2375-80. [Google Scholar]
[23]. Leong JW, Chase JM1, Romee R, Schneider SE, Sullivan RP, Cooper MA, Preactivation with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells Biol Blood Marrow Transplant 2014 20(4):463-73. [Google Scholar]
[24]. Schroder K, Hertzog PJ, Ravasi T, Hume DA, Interferon-gamma: an overview of signals, mechanisms and functions J Leukoc Biol 2004 75(2):163-89. [Google Scholar]
[25]. Chiang SC, Theorell J, Entesarian M, Meeths M, Mastafa M, Al-Herz W, Comparison of primary human cytotoxic T-cell and natural killer cell responses reveal similar molecular requirements for lytic granule exocytosis but differences in cytokine production Blood 2013 121(8):1345-56. [Google Scholar]
[26]. Lodoen MB, Lanier LL, Viral modulation of NK cell immunity Nature Reviews Microbiology 2005 3(1):59-69. [Google Scholar]
[27]. Champsaur M, Lanier LL, Effect of NKG2D ligand expression on host immune responses Immunol Rev 2010 235(1):267-85. [Google Scholar]
[28]. Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T, Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium Proc Natl Acad Sci USA 1996 93:12445-50. [Google Scholar]
[29]. McFarland BJ, Kortemme T, Yu SF, Baker D, Strong RK, Symmetry Recognizing Asymmetry: Analysis of the Interactions between the C-Type Lectin-like Immunoreceptor NKG2D and MHC Class I-like Ligands Structure 2003 11:411-22. [Google Scholar]
[30]. Amenu A, Hadush T, Tilahun A, Teshale A, Getachew A, Natural killer cell and its potential therapeutic role in cancer: a review Academic Journal of Cancer Research 2016 9(3):50-57. [Google Scholar]
[31]. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, IFNγand lymphocytes prevent primary tumour development and shape tumour immunogenicity Nature 2001 410(6832):1107-11. [Google Scholar]
[32]. Dunn GP, Old LJ, Schreiber RD, The immunobiology of cancer immunosurveillance and immunoediting Immunity 2004 21(2):137-48. [Google Scholar]
[33]. Smyth MJ, Dunn GP, Schreiber RD, Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumour development and shaping tumour immunogenicity Adv Immunol 2006 90:1-50. [Google Scholar]
[34]. Swann JB, Smyth MJ, Immune surveillance of tumours J Clin Invest 2007 117:1137-46. [Google Scholar]
[35]. Une C, Andersson J, Örn A, Role of IFN-α/βand IL-12 in the activation of natural killer cells and interferon-γproduction during experimental infection with Trypanosoma cruzi Clin Exp Immunol 2003 134(2):195-201. [Google Scholar]
[36]. Weiss JM, Subleski JJ, Wigginton JM, Wiltrout RH, Immunotherapy of cancer by IL-12-based cytokine combinations Expert Opin Biol Ther 2007 7(11):1705-21. [Google Scholar]
[37]. Bui JD, Schreiber RD, Cancer immunosurveillance, immunoediting and inflammation: independent or interdependent processes? Curr Opin Immunol 2007 19(2):203-08. [Google Scholar]
[38]. Waldhauer I, Steinle A, NK cells and cancer immunosurveillance Oncogene 2008 27(45):5932-43. [Google Scholar]
[39]. Bachanova V, Miller JS, NK Cells in Therapy of Cancer Crit Rev Oncog 2014 19(0):133-41. [Google Scholar]
[40]. Ricci MS, Zong WX, Chemotherapeutic approaches for targeting cell death pathways Oncologist 2006 11(4):342-57. [Google Scholar]
[41]. Cheng M, Chen Y, Xiao W, Sun R, Tian Z, NK cell-based immunotherapy for malignant diseases Cell Mol Immunol 2013 10:230-52. [Google Scholar]
[42]. Wang W, Erbe AK, Hank JA, Morris ZS, Sondel PM, NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity in Cancer Immunotherapy Front Immunol 2015 6:368 [Google Scholar]
[43]. Jordan S, OrangeNatural killer cell deficiency J Allergy Clin Immunol 2013 132(3):515-26. [Google Scholar]
[44]. Orange JS, Brodeur SR, Jain A, Bonilla FA, Schneider LC, Kretschmer R, Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations J Clin Invest 2002 109:1501-09. [Google Scholar]
[45]. Komiyama A, Kawai H, Yabuhara A, Mitsuhiko Y, Miyagawa Y, Ota M, Natural killer cell immunodeficiency in siblings: defective killing in the absence of natural killer cytotoxic factor activity in natrual killer and lymphokine-activated killer cytotoxicities Pediatr 1990 85:323-30. [Google Scholar]
[46]. Orange JS, Unraveling human natural killer cell deficiency J Clin Invest 2012 122:798-801. [Google Scholar]
[47]. Jandus C, Boligan KF, Chijioke O, Liu H, Dahlhaus M, Demoulins T, Interactions between Siglec-7/9 receptors and ligands influence NK cell–dependent tumour immunosurveillance J Clin Invest 2014 124(4):1810-20. [Google Scholar]
[48]. Belisle J, Horibata S, Jennifer GA, Identification of Siglec-9 as the receptor for MUC16 on human NK cells, B cells, and monocytes Mol Cancer 2010 9(1):118 [Google Scholar]
[49]. Hudak JE, Canham SM, Bertozzi CR, Glycocalyx engineering reveals a Siglec-based mechanism for NK cell immunoevasion Nat Chem Biol 2014 10(1):69-75. [Google Scholar]
[50]. Shao JY, Yin WW, Zhang QF, Liu Q, Peng ML, Hu HD, Siglec-7 Defines a Highly Functional Natural Killer Cell Subset and Inhibits Cell-Mediated Activities Scandinavian Journal of Immunology 2016 84(3):182-90. [Google Scholar]
[51]. Den Otter W, Jacobs JJ, Battermann JJ, Hordijk GJ, Krastev Z, Moiseeva EV, Local therapy of cancer with free IL-2 Cancer Immunol Immunother 2008 57(7):931-50. [Google Scholar]
[52]. Jacobsen SE, Okkenhaug C, Myklebust J, Veiby OP, Lyman SD, The FLT3 ligand potently and directly stimulates the growth and expansion of primitive murine bone marrow progenitor cells in vitro: synergistic interactions with interleukin (IL) 11, IL-12, and other hematopoietic growth factors J Exp Med 1995 181(4):1357-63. [Google Scholar]
[53]. McKenna HJ, de Vries P, Brasel K, Lyman SD, Williams DE, Effect of flt3 ligand on the ex vivo expansion of human CD34+hematopoietic progenitor cells Blood 1995 86(9):3413-20. [Google Scholar]
[54]. Parihar R, Dierksheide J, Hu Y, Carson WE, IL-12 enhances the natural killer cell cytokine response to Ab-coated tumour cells J Clin Invest 2002 110(7):983-92. [Google Scholar]
[55]. Kannan Y, Yu J, Raices RM, Seshadri S, Wei M, Caligiuri MA, IκBζaugments IL-12–and IL-18–mediated IFN-γproduction in human NK cells Blood 2011 117(10):2855-63. [Google Scholar]
[56]. Fanger NA, Maliszewski CR, Schooley K, Griffith TS, Human dendritic cells mediate cellular apoptosis via tumour necrosis factor–related apoptosis-inducing ligand (TRAIL) J Exp Med 1999 190(8):1155-64. [Google Scholar]
[57]. Mogensen TH, Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses Clin Microbiol Rev 2009 22(2):240-43. [Google Scholar]
[58]. Cheng M, Chen Y, Xiao W, Sun R, Tian Z, NK cell-based immunotherapy for malignant diseases Cell Mol Immune 2013 10(3):230-52. [Google Scholar]
[59]. Koehl U, Kalberer C, Spanholtz J, Lee DA, Miller JS, Cooley S, Advances in clinical NK cell studies: donor selection, manufacturing and quality control Oncoimmunology 2016 5(4):e1115178 [Google Scholar]
[60]. Sakamoto N, Ishikawa T, Kokura S, Okayama T, Oka K, Ideno M, Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer J Trans Med 2015 13(1):277 [Google Scholar]
[61]. Dahlberg CI, Sarhan D, Chrobok M, Duru AD, Alici E, Natural killer cell-based therapies targeting cancer: possible strategies to gain and sustain anti-tumour activity Front Immunol 2015 6:605 [Google Scholar]
[62]. Nguyen S, Kuentz M, Vernant JP, Dhedin N, Bories D, Debre P, Involvement of mature donor T cells in the NK cell reconstitution after haploidentical hematopoietic stem-cell transplantation Leukemia 2008 22(2):344-52. [Google Scholar]
[63]. Knorr DA, Ni Z, Hermanson D, Hexum MK, Bendzick L, Cooper LJ, Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy Stem Cells Transl Med 2013 2:274-83. [Google Scholar]
[64]. Luevano M, Domogala A, Blundell M, Jackson N, Pedroza-Pacheco I, Derniame S, Frozen cord blood hematopoietic stem cells differentiate into higher numbers of functional natural killer cells in vitro than mobilized hematopoietic stem cells or freshly isolated cord blood hematopoietic stem cells PloS one 2014 9(1):e87086 [Google Scholar]
[65]. Knorr D, Bachanova V, Verneris MR, Miller JS, Clinical utility of natural killer cells in cancer therapy and transplantation Semin Immunol 2014 26(2):161-72. [Google Scholar]
[66]. Ni Z, Knorr DA, Clouser CL, Hexum MK, Southern P, Mansky LM, Human pluripotent stem cells produce natural killer cells that mediate anti-HIV-1 activity by utilizing diverse cellular mechanisms J Virol 2011 85(1):43-50. [Google Scholar]
[67]. Hermanson DL, Bendzick L, Pribyl L, McCullar V, Vogel RI, Miller JS, Induced pluripotent stem cell-derived natural killer cells for treatment of ovarian cancer Stem cells (Dayton, Ohio) 2016 34(1):93-101. [Google Scholar]
[68]. https://en.wikipedia.org/wiki/Antibody-dependent_cell-mediated_cytotoxicity Last accessed on December 2016 [Google Scholar]
[69]. Weiner LM, Surana R, Wang S, Antibodies and cancer therapy: versatile platforms for cancer immunotherapy Nat Rev Immunol 2010 10(5):317-27. [Google Scholar]