Abstract
Numerous newly identified activating and inhibitory NK cell receptors and their engagement by cognate ligands on target tumor cells regulate NK cell antitumor activity. Alterations in NK cell receptor expression and signaling underlie diminished cytotoxic NK cell function. Cytokines, IFN-α, IL-2, IL-12, IL-15 and IL-18, applied systemically and for ex vivo activation and expansion of NK cells have improved NK cell antitumor activity by increasing the expression of NK cell activating receptors and by inducing cytotoxic effector molecules. Moreover, it has been recognized that classical and novel pharmacological agents upregulate cognate ligands for activating receptors on tumor cells and provide better NK cell antitumor response. Some other immunotherapeutic approaches in cancer in the setting of donor-recipient KIR/HLA mismatch have evolved with the aim to potentiate NK cell activity in allogeneic hematopoietic stem cell transplantation that lead to beneficial graft vs. tumor effect. Therefore, better understanding of NK cell activating and inhibitory receptor biology is needed to assist in developing novel approaches to effectively manipulate NK cells and create effective NK cell-based immunotherapy for treatment of cancer patients.
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References
Caligiuri MA. Human natural killer cells. Blood. 2008;112(3):461–9.
Cortez VS, Robinette ML, Colonna M. Innate lymphoid cells: new insights into function and development. Curr Opin Immunol. 2015;32:71–7.
Freud AG, Yokohama A, Becknell B, Lee MT, Mao HC, Ferketich AK, Caligiuri MA. Evidence for discrete stages of human natural killer cell differentiation in vivo. J Exp Med. 2006;203(4):1033–43.
Lopez-Vergès S, Milush JM, Pandey S, York VA, Arakawa-Hoyt J, Pircher H, Norris PJ, et al. CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset. Blood. 2010;116(19):3865–74.
Jaeger BN, Vivier E. When NK cells overcome their lack of education. J Clin Invest. 2012;122(9):3053–6.
Stojanovic A, Correia MP, Cerwenka A. Shaping of NK cell responses by the tumor microenvironment. Cancer Microenviron. 2013;6(2):135–46.
Höglund P, Brodin P. Current perspectives of natural killer cell education by MHC class I molecules. Nat Rev Immunol. 2010;10(10):724–34.
Farag SS, Caligiuri MA. Human natural killer cell development and biology. Blood Rev. 2006;20(3):123–37.
Campbell KS, Purdy AK. Structure/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutations. Immunology. 2011;132(3):315–25.
Konjević G, Schlesinger B, Cheng L, Olsen KJ, Podack ER, Spužić I. Analysis of perforin expression in human peripheral blood lymphocytes, CD56+ natural killer cell subsets and its induction by interleukin-2. Immunol Invest. 1995;24(3):499–507.
Konjević G, Jurišić V, Jović V, Vuletić A, Mirjačić Martinović K, Radenković S, Spužić I. Investigation of NK cell function and their modulation in different malignancies. Immunol Res. 2012;52(1–2):139–56.
Podack ER, Dennert G. Assembly of two types of tubules with putative cytolytic function by cloned natural killer cells. Nature. 1983;302(5907):442–5.
Khar A, Varalakshmi C, Pardhasaradhi BV, Mubarak Ali A, Kumari AL. Depletion of the natural killer cell population in the peritoneum by AK-5 tumor cell overexpressing fas-ligand: a mechanism of immune evasion. Cell Immunol. 1998;189(2):85–91.
Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, Yokoyama WM, Ugolini S. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331(6013):44–9.
Uhrberg M, Valiante NM, Shum BP, Shilling HG, Lienert-Weidenbach K, Corliss B, Tyan D, et al. Human diversity in killer cell inhibitory receptor genes. Immunity. 1997;7(6):753–63.
Guia S, Jaeger BN, Piatek S, Mailfert S, Trombik T, Fenis A, Chevrier N, et al. Confinement of activating receptors at the plasma membrane controls natural killer cell tolerance. Sci Signal. 2011;4(167):ra21.
Purdy AK, Campbell KS. Natural killer cells and cancer: regulation by the killer cell Ig-like receptors (KIR). Cancer Biol Ther. 2009;8(32):2211–20.
Boyton RJ, Altmann DM. Natural killer cells, killer immunoglobulin-like receptors and human leucocyte antigen class I in disease. Clin Exp Immunol. 2007;149(1):1–8.
Naumova E, Mihaylova A, Ivanova M, Mihailova S. Impact of KIR/HLA ligand combinations on immune responses in malignant melanoma. Cancer Immunol Immunother. 2007;56(1):95–100.
Campillo JA, Martínez-Escribano JA, Moya-Quiles MR, Marín LA, Muro M, Guerra N, Parrado A, et al. Natural killer receptors on CD8 T cells and natural killer cells from different HLA-C phenotypes in melanoma patients. Clin Cancer Res. 2006;12(16):4822–31.
Peng YP, Zhu Y, Zhang JJ, Xu ZK, Qian ZY, Dai CC, Jiang KR, et al. Comprehensive analysis of the percentage of surface receptors and cytotoxic granules positive natural killer cells in patients with pancreatic cancer, gastric cancer, and colorectal cancer. J Transl Med. 2013;11:262.
Konjević G, Mirjacić Martinović K, Jurisić V, Babović N, Spuzić I. Biomarkers of suppressed natural killer (NK) cell function in metastatic melanoma: decreased NKG2D and increased CD158a receptors on CD3−CD16+ NK cells. Biomarkers. 2009;14(4):258–70.
Varker KA, Terrell CE, Welt M, Suleiman S, Thornton L, Andersen BL, Carson WE 3rd. Impaired natural killer cell lysis in breast cancer patients with high levels of psychological stress is associated with altered expression of killer immunoglobulin-like receptors. J Surg Res. 2007;139(1):36–44.
Al Omar SY, Marshall E, Middleton D, Christmas SE. Increased killer immunoglobulin-like receptor expression and functional defects in natural killer cells in lung cancer. Immunology. 2011;133(1):94–104.
Mirjačić Martinović K, Konjević G, Babović N, Inić M. The stage dependent changes in NK cell activity and the expression of activating and inhibitory NK cell receptors in melanoma patients. J Surg Res. 2011;171(2):637–49.
Vuletić A, Jurišić V, Jovanić I, Milovanović Z, Nikolić S, Konjević G. Distribution of several activating and inhibitory receptors on CD3(−)CD56(+) NK cells in regional lymph nodes of melanoma patients. J Surg Res. 2013;183(2):860–8.
Stern-Ginossar N, Mandelboim O. An integrated view of the regulation of NKG2D ligands. Immunology. 2009;128(1):1–6.
López-Larrea C, Suárez-Alvarez B, López-Soto A, López-Vázquez A, Gonzalez S. The NKG2D receptor: sensing stressed cells. Trends Mol Med. 2008;14(4):179–89.
Zafirova B, Wensveen FM, Gulin M, Polić B. Regulation of immune cell function and differentiation by the NKG2D receptor. Cell Mol Life Sci. 2011;68(21):3519–29.
Wu J, Song Y, Bakker AB, Bauer S, Spies T, Lanier LL, Phillips JH. An activating immunoreceptor complex formed by NKG2D and DAP10. Science. 1999;285(5428):730–2.
Hayakawa Y, Smyth MJ. NKG2D and cytotoxic effector function in tumor immune surveillance. Semin Immunol. 2006;18:176–85.
Mamessier E, Sylvain A, Bertucci F, Castellano R, Finetti P, Houvenaeghel G, Charaffe-Jaufret E, et al. Human breast tumor cells induce self-tolerance mechanisms to avoid NKG2D-mediated and DNAM-mediated NK cell recognition. Cancer Res. 2011;71(21):6621–32.
Garcia-Iglesias T, Del Toro-Arreola A, Albarran-Somoza B, Del Toro-Arreola S, Sanchez-Hernandez PE, Ramirez-Dueñas MG, Balderas-Peña LM. Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions. BMC Cancer. 2009;9:186.
de Kruijf EM, Sajet A, van Nes JG, Putter H, Smit VT, Eagle RA, Jafferji I, et al. NKG2D ligand tumor expression and association with clinical outcome in early breast cancer patients: an observational study. BMC Cancer. 2012;12:24.
Shen Y, Lu C, Tian W, Wang L, Cui B, Jiao Y, Ma C. Possible association of decreased NKG2D expression levels and suppression of the activity of natural killer cells in patients with colorectal cancer. Int J Oncol. 2012;40(4):1285–90.
He S, Yin T, Li D, Gao X, Wan Y, Ma X, Ye T, et al. Enhanced interaction between natural killer cells and lung cancer cells: involvement in gefitinib-mediated immunoregulation. J Transl Med. 2013;11:186.
Zhang Z, Su T, He L, Wang H, Ji G, Liu X, Zhang Y, Dong G. Identification and functional analysis of ligands for natural killer cell activating receptors in colon carcinoma. Tohoku J Exp Med. 2012;226(1):59–68.
Schiavoni G, Gabriele L, Mattei F. The tumor microenvironment: a pitch for multiple players. Front Oncol. 2013;3:90.
Chitadze G, Bhat J, Lettau M, Janssen O, Kabelitz D. Generation of soluble NKG2D ligands: proteolytic cleavage, exosome secretion and functional implications. Scand J Immunol. 2013;78(2):120–9.
Konjević G, Mirjacić Martinović K, Vuletić A, Jurisić V, Spuzić I. Distribution of several activating and inhibitory receptors on CD3−CD16+ NK cells and their correlation with NK cell function in healthy individuals. J Membr Biol. 2009;230(3):113–23.
Konjević G, Mirjacić Martinović K, Vuletić A, Jović V, Jurisić V, Babović N, Spuzić I. Low expression of CD161 and NKG2D activating NK receptor is associated with impaired NK cell cytotoxicity in metastatic melanoma patients. Clin Exp Metastasis. 2007;24(1):1–11.
Delahaye NF, Rusakiewicz S, Martins I, Menard C, Roux S, Lyonnet L, Paul P, et al. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat Med. 2011;17(6):700–7.
Narni-Mancinelli E, Jaeger BN, Bernat C, Fenis A, Kung S, De Gassart A, Mahmood S, et al. Tuning of natural killer cell reactivity by NKp46 and Helios calibrates T cell responses. Science. 2012;335(6066):344–8.
Rosental B, Brusilovsky M, Hadad U, Oz D, Appel MY, Afergan F, Yossef R, et al. Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44. J Immunol. 2011;187(11):5693–702.
Hudspeth K, Silva-Santos B, Mavilio D. Natural cytotoxicity receptors: broader expression patterns and functions in innate and adaptive immune cells. Front Immunol. 2013;4:69.
Pietra G, Manzini C, Rivara S, Vitale M, Cantoni C, Petretto A, Balsamo M, et al. Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity. Cancer Res. 2012;72(6):1407–15.
Fiegler N, Textor S, Arnold A, Rölle A, Oehme I, Breuhahn K, Moldenhauer G, et al. Downregulation of the activating NKp30 ligand B7–H6 by HDAC inhibitors impairs tumor cell recognition by NK cells. Blood. 2013;122(5):684–93.
Reiners KS, Topolar D, Henke A, Simhadri VR, Kessler J, Sauer M, Bessler M, et al. Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity. Blood. 2013;121(18):3658–65.
Sanchez-Correa B, Morgado S, Gayoso I, Bergua JM, Casado JG, Arcos MJ, Bengochea ML, et al. Human NK cells in acute myeloid leukaemia patients: analysis of NK cell-activating receptors and their ligands. Cancer Immunol Immunother. 2011;60(8):1195–205.
Rosental B, Hadad U, Brusilovsky M, Campbell KS, Porgador A. A novel mechanism for cancer cells to evade immune attack by NK cells: the interaction between NKp44 and proliferating cell nuclear antigen. Oncoimmunology. 2012;1(4):572–4.
Pegram HJ, Andrews DM, Smyth MJ, Darcy PK, Kershaw MH. Activating and inhibitory receptors of natural killer cells. Immunol Cell Biol. 2011;89(2):216–24.
Lakshmikanth T, Burke S, Ali TH, Kimpfler S, Ursini F, Ruggeri L, Capanni M, et al. NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo. J Clin Invest. 2009;119(5):1251–63.
Morgado S, Sanchez-Correa B, Casado JG, Duran E, Gayoso I, Labella F, Solana R, Tarazona R. NK cell recognition and killing of melanoma cells is controlled by multiple activating receptor-ligand interactions. J Innate Immun. 2011;3(4):365–73.
Pende D, Castriconi R, Romagnani P, Spaggiari GM, Marcenaro S, Dondero A, Lazzeri E, et al. 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(5):2030–6.
Morisaki T, Onishi H, Katano M. Cancer immunotherapy using NKG2D and DNAM-1 systems. Anticancer Res. 2012;32(6):2241–7.
Mirjačić Martinović KM, Babović NLJ, Džodić RR, Jurišić VB, Tanić NT, Konjević GM. Decreased expression of NKG2D, NKp46, DNAM-1 receptors, and intracellular perforin and STAT-1 effector molecules in NK cells and their dim and bright subsets in metastatic melanoma patients. Melanoma Res. 2014;24(4):295–304.
Warren HS, Kinnear BF. Quantitative analysis of the effect of CD16 ligation on human NK cell proliferation. J Immunol. 1999;162(2):735–42.
Nagler A, Lanier LL, Cwirla S, Phillips JH. Comparative studies of human FcRIII-positive and negative natural killer cells. J Immunol. 1989;143(10):3183–91.
Lanier LL. Natural killer cell receptor signaling. Curr Opin Immunol. 2003;15(3):308–14.
Vivier E, Nunes JA, Vely F. Natural killer cell signaling pathways. Science. 2004;306(5701):1517–9.
Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, Carson WE, Caligiuri MA. Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood. 2001;97(10):3146–51.
Gryzwacz B, Kataria N, Verneris MR. CD56dimCD16+ NK cells downregulate CD16 following target cell induced activation of matrix metaloprteinases. Letter to the editor. Leukemia. 2007;21(2):356–9.
Romee R, Foley B, Lenvik T, Wang Y, Zhang B, Ankarlo D, Luo X, et al. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood. 2013;121(18):3599–608.
Braud VM, Allan DS, O’Callaghan CA, Söderström K, D’Andrea A, Ogg GS, Lazetic S, et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature. 1998;391(6669):795–9.
Iwaszko M, Bogunia-Kubik K. Clinical significance of the HLA-E and CD94/NKG2 interaction. Arch Immunol Ther Exp (Warsz). 2011;59(5):353–67.
Michaelsson J, Teixeira de Matos C, Achour A, Lanier LL, Karre K, Soderstrom K. A signal peptide derived from hsp60 binds HLA-E and interferes with CD94/NKG2A recognition. J Exp Med. 2002;196(11):1403–14.
Bossard C, Bézieau S, Matysiak-Budnik T, Volteau C, Laboisse CL, Jotereau F, Mosnier JF. HLA-E/β2 microglobulin overexpression in colorectal cancer is associated with recruitment of inhibitory immune cells and tumor progression. Int J Cancer. 2012;131(4):855–63.
Colonna M, Nakajima H, Cella M. Inhibitory and activating receptors involved in immune surveillance by human NK and myeloid cells. J Leukoc Biol. 1999;66(5):718–22.
Heidenreich S, Zu Eulenburg C, Hildebrandt Y, Stübig T, Sierich H, Badbaran A, Eiermann TH, et al. Impact of the NK cell receptor LIR-1 (ILT-2/CD85j/LILRB1) on cytotoxicity against multiple myeloma. Clin Dev Immunol. 2012;2012:652130.
Kirkham CL, Carlyle JR. Complexity and diversity of the NKR-P1: Clr (Klrb1:Clec2) recognition systems. Front Immunol. 2014;5:214.
Montaldo E, Vitale C, Cottalasso F, Conte R, Glatzer T, Ambrosini P, Moretta L, Mingari MC. Human NK cells at early stages of differentiation produce CXCL8 and express CD161 molecule that functions as an activating receptor. Blood. 2012;119(17):3987–96.
Azzoni L, Zatsepina O, Abebe B, Bennett IM, Kanakaraj P, Perussia B. Differential transcriptional regulation of CD161 and a novel gene, 197/15a, by IL-2, IL-15, and IL-12 in NK and T cells. J Immunol. 1998;161(7):3493–500.
Lanier LL, Chang C, Phillips JH. Human NKR-P1A. A disulfide-linked homodimer of the C-type lectin superfamily expressed by a subset of NK and T lymphocytes. J Immunol. 1994;153(6):2417–28.
Aldemir H, Prod’homme V, Dumaurier MJ, Retiere C, Poupon G, Cazareth J, Bihl F, Braud VM. Cutting edge: lectin-like transcript 1 is a ligand for the CD161 receptor. J Immunol. 2005;175(12):7791–5.
Rosen DB, Bettadapura J, Alsharifi M, Mathew PA, Warren HS, Lanier LL. Cutting edge: lectin-like transcript-1 is a ligand for the inhibitory human NKR-P1A receptor. J Immunol. 2005;175(12):7796–9.
Ryan JC, Seaman WE. Divergent functions of lectin-like receptors on NK cells. Immunol Rev. 1997;155:79–89.
Cheng M, Chen Y, Xiao W, Sun R, Tian Z. NK cell-based immunotherapy for malignant diseases. Cell Mol Immunol. 2013;10(3):230–52.
Moretta L, Montaldo E, Vacca P, Del Zotto G, Moretta F, Merli P, Locatelli F, Mingari MC. Human natural killer cells: origin, receptors, function, and clinical applications. Int Arch Allergy Immunol. 2014;164(4):253–64.
Velardi A, Ruggeri L, Moretta A, Moretta L. NK cells: a lesson from mismatched hematopoietic transplantation. Trends Immunol. 2002;23(9):438–44.
Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295(5562):2097–100.
Ruggeri L, Capanni M, Casucci M, Volpi I, Tosti A, Perruccio K, Urbani E, et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood. 1999;94(1):333–9.
Miller JS, Cooley S, Parham P, Farag SS, Verneris MR, McQueen KL, Guethlein LA, et al. Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic HCT. Blood. 2007;109(11):5058–61.
Hsu KC, Pinto-Agnello C, Gooley T, Malkki M, Dupont B, Petersdorf EW. Hematopoietic stem cell transplantation: killer immunoglobulin-like receptor component. Tissue Antigens. 2007;69:42–5.
McQueen KL, Dorighi KM, Guethlein LA, Wong R, Sanjanwala B, Parham P. Donor-recipient combinations of group A and B KIR haplotypes and HLA class I ligand affect the outcome of HLA-matched, sibling donor hematopoietic cell transplantation. Hum Immunol. 2007;68(5):309–23.
Venstrom JM, Pittari G, Gooley TA, Chewning JH, Spellman S, Haagenson M, Gallagher MM, et al. HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1. N Engl J Med. 2012;367(9):805–16.
Benson DM Jr, Caligiuri MA. Killer immunoglobulin-like receptors and tumor immunity. Cancer Immunol Res. 2014;2(2):99–104.
Hallett WH, Ames E, Alvarez M, Barao I, Taylor PA, Blazar BR, Murphy WJ. Combination therapy using IL-2 and anti-CD25 results in augmented natural killer cell-mediated antitumor responses. Biol Blood Marrow Transplant. 2008;14(10):1088–99.
Ames E, Murphy WJ. Advantages and clinical applications of natural killer cells in cancer immunotherapy. Cancer Immunol Immunother. 2014;63(1):21–8.
Konjević G, Mirjačić Martinović K, Vuletić A, Radenković S. Novel aspects of in vitro IL-2 or IFN-α enhanced NK cytotoxicity of healthy individuals based on NKG2D and CD161 NK cell receptor induction. Biomed Pharmacother. 2010;64(10):663–71.
Zwirner NW, Domaica CI. Cytokine regulation of natural killer cell effector functions. BioFactors. 2010;36(4):274–88.
Vuletić AM, Jovanić IP, Jurišić VB, Milovanović ZM, Nikolić SS, Tanić NT, Konjević GM. In-vitro activation of natural killer cells from regional lymph nodes of melanoma patients with interleukin-2 and interleukin-15. Melanoma Res. 2015;25(1):22–34.
Park YP, Choi SC, Kiesler P, Gil-Krzewska A, Borrego F, Weck J, Krzewski K, Coligan JE. Complex regulation of human NKG2D-DAP10 cell surface expression: opposing roles of the γc cytokines and TGF-β1. Blood. 2011;118(11):3019–27.
Konjević G, Jović V, Radulović S, Jelić S, Dzodić R, Spuzić I. Therapeutic implications of the kinetics of immunomodulation during single or combined treatment of melanoma patients with dacarbazine and interferon-alpha. Neoplasma. 2001;48(3):175–81.
Konjević G, Jović V, Vuletić A, Radulović S, Jelić S, Spuzić I. CD69 on CD56+ NK cells and response to chemoimmunotherapy in metastatic melanoma. Eur J Clin Invest. 2007;37(11):887–96.
Ni J, Miller M, Stojanovic A, Garbi N, Cerwenka A. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. J Exp Med. 2012;209(13):2351–65.
Leong JW, Chase JM, Romee R, Schneider SE, Sullivan RP, Cooper MA, Fehniger TA. 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.
Konjević G, Spuzić I. Stage dependence of NK cell activity and its modulation by interleukin 2 in patients with breast cancer. Neoplasma. 1993;40(2):81–5.
Konjević G, Mirjačić Martinović K, Vuletić A, Babović N. In-vitro IL-2 or IFN-α-induced NKG2D and CD161 NK cell receptor expression indicates novel aspects of NK cell activation in metastatic melanoma patients. Melanoma Res. 2010;20(6):459–67.
Mirjačić Martinović K, Babović N, Džodić R, Jurišić V, Matković S, Konjević G. Favorable in vitro effects of combined IL-12 and IL-18 treatment on NK cell cytotoxicity and CD25 receptor expression in metastatic melanoma patients. J Transl Med. 2015;13:120.
Morris JC, Tan AR, Olencki TE, Shapiro GI, Dezube BJ, Reiss M, Hsu FJ, et al. Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFβ) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS ONE. 2014;9:e90353.
Zitvogel L, Tesniere A, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of anticancer chemotherapy. Bull Acad Natl Med. 2008;192(7):1469–87.
Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72.
Mentlik James A, Cohen AD, Campbell KS. Combination immune therapies to enhance anti-tumor responses by NK cells. Front Immunol. 2013;4:481.
Kohga K, Takehara T, Tatsumi T, Ishida H, Miyagi T, Hosui A, Hayashi N. Sorafenib inhibits the shedding of major histocompatibility complex class I-related chain A on hepatocellular carcinoma cells by down-regulating a disintegrin and metalloproteinase 9. Hepatology. 2010;51(4):1264–73.
Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19(19):5300–9.
Benson DM Jr, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, Baiocchi RA, et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood. 2010;116(13):2286–94.
Sentman CL, Meehan KR. NKG2D CARs as cell therapy for cancer. Cancer J. 2014;20:156–9.
Seidel UJ, Schlegel P, Lang P. Natural killer cell mediated antibody-dependent cellular cytotoxicity in tumor immunotherapy with therapeutic antibodies. Front Immunol. 2013;4:76.
Campbell KS, Hasegawa J. Natural killer cell biology: an update and future directions. J Allergy Clin Immunol. 2013;132(3):536–44.
Bryceson YT, March ME, Ljunggren HG, Long EO. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood. 2006;107(1):159–66.
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This study was supported by the grants of the Ministry of Education, Science and Technology of the Republic of Serbia: Grant Number 41031 and Grant Number 175056.
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Konjević, G., Vuletić, A. & Mirjačić Martinović, K. Natural killer cell receptors: alterations and therapeutic targeting in malignancies. Immunol Res 64, 25–35 (2016). https://doi.org/10.1007/s12026-015-8695-4
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DOI: https://doi.org/10.1007/s12026-015-8695-4