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Natural killer cells as a promising therapeutic target for cancer immunotherapy

Abstract

Natural killer (NK) cells are innate lymphoid cells that provide early protection against cancer development via their selectivity to kill abnormal cells undergoing cellular transformation without the need for prior stimulation. Given the correlation between NK cell dysfunction and cancer prognosis, restoration of endogenous NK cells in the tumor microenvironment or adoptive transfer of NK cells with improved function holds great promise in cancer treatment. Furthermore, MHC-unrestricted tumor lysis by NK cells complements the MHC-restricted killing of tumor cells by cytotoxic T cells, thus positioning NK cells as an alternative or complementary therapeutic target for cancers that are refractory to T cell-based therapy. Although previous therapeutic strategies have focused on the manipulation of NK cell inhibitory receptors, recent advances in our understanding of NK cell activation have provided additional promising strategies to enhance NK cell reactivity against cancer. These approaches include targeting immunosuppressive mechanisms in the tumor microenvironment, such as immune checkpoint receptors, and further enhancing NK cell activation via modulation of intracellular checkpoint molecules or incorporation of tumor-directed chimeric antigen receptors. Thus, an in-depth understanding of NK cell activation will facilitate the optimal design of therapeutic strategies against refractory cancers, possibly in rational and synergistic combination with other therapies.

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References

  1. Abel AM, Yang C, Thakar MS, Malarkannan S (2018) Natural killer cells: development, maturation, and clinical utilization. Front Immunol 9:1869

  2. Anderson AC, Joller N, Kuchroo VK (2016) Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44:989–1004

  3. Andre P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T, Blery M, Bonnafous C, Gauthier L, Morel A, Rossi B, Remark R, Breso V, Bonnet E, Habif G, Guia S, Lalanne AI, Hoffmann C, Lantz O, Fayette J, Boyer-Chammard A, Zerbib R, Dodion P, Ghadially H, Jure-Kunkel M, Morel Y, Herbst R, Narni-Mancinelli E, Cohen RB, Vivier E (2018) Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 175(1731–1743):e13

  4. Anfossi N, Andre P, Guia S, Falk CS, Roetynck S, Stewart CA, Breso V, Frassati C, Reviron D, Middleton D, Romagne F, Ugolini S, Vivier E (2006) Human NK cell education by inhibitory receptors for MHC class I. Immunity 25:331–342

  5. Angka L, Martel AB, Kilgour M, Jeong A, Sadiq M, De Souza CT, Baker L, Kennedy MA, Kekre N, Auer RC (2018) Natural killer cell IFNgamma secretion is profoundly suppressed following colorectal cancer surgery. Ann Surg Oncol 25:3747–3754

  6. Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F, Ruggeri L, Barbabietola G, Aristei C, Latini P, Reisner Y, Martelli MF (1998) Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 339:1186–1193

  7. 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 (2014) Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. Blood 123:3855–3863

  8. Bachanova V, Sarhan D, Defor TE, Cooley S, Panoskaltsis-Mortari A, Blazar BR, Curtsinger JM, Burns L, Weisdorf DJ, Miller JS (2018) Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells. Cancer Immunol Immunother 67:483–494

  9. Balsamo M, Scordamaglia F, Pietra G, Manzini C, Cantoni C, Boitano M, Queirolo P, Vermi W, Facchetti F, Moretta A, Moretta L, Mingari MC, Vitale M (2009) Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity. Proc Natl Acad Sci USA 106:20847–20852

  10. Barker HE, Paget JT, Khan AA, Harrington KJ (2015) The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer 15:409–425

  11. Baxevanis CN, Papilas K, Dedoussis GV, Pavlis T, Papamichail M (1994) Abnormal cytokine serum levels correlate with impaired cellular immune responses after surgery. Clin Immunol Immunopathol 71:82–88

  12. Beldi-Ferchiou A, Lambert M, Dogniaux S, Vely F, Vivier E, Olive D, Dupuy S, Levasseur F, Zucman D, Lebbe C, Sene D, Hivroz C, Caillat-Zucman S (2016) PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma. Oncotarget 7:72961–72977

  13. Bell CJ, Sun Y, Nowak UM, Clark J, Howlett S, Pekalski ML, Yang X, Ast O, Waldhauer I, Freimoser-Grundschober A, Moessner E, Umana P, Klein C, Hosse RJ, Wicker LS, Peterson LB (2015) Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells. J Autoimmun 56:66–80

  14. Benson DM Jr, Cohen AD, Jagannath S, Munshi NC, Spitzer G, Hofmeister CC, Efebera YA, Andre P, Zerbib R, Caligiuri MA (2015) A phase I trial of the anti-KIR antibody IPH2101 and lenalidomide in patients with relapsed/refractory multiple myeloma. Clin Cancer Res 21:4055–4061

  15. Bloch-Queyrat C, Fondaneche MC, Chen R, Yin L, Relouzat F, Veillette A, Fischer A, Latour S (2005) Regulation of natural cytotoxicity by the adaptor SAP and the Src-related kinase Fyn. J Exp Med 202:181–192

  16. Bottino C, Castriconi R, Pende D, Rivera P, Nanni M, Carnemolla B, Cantoni C, Grassi J, Marcenaro S, Reymond N, Vitale M, Moretta L, Lopez M, Moretta A (2003) Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med 198:557–567

  17. Brandt CS, Baratin M, Yi EC, Kennedy J, Gao Z, Fox B, Haldeman B, Ostrander CD, Kaifu T, Chabannon C, Moretta A, West R, Xu W, Vivier E, Levin SD (2009) The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. J Exp Med 206:1495–1503

  18. Bryceson YT, March ME, Ljunggren HG, Long EO (2006a) Activation, coactivation, and costimulation of resting human natural killer cells. Immunol Rev 214:73–91

  19. Bryceson YT, March ME, Ljunggren HG, Long EO (2006b) Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood 107:159–166

  20. Bryceson YT, Ljunggren HG, Long EO (2009) Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors. Blood 114:2657–2666

  21. Burshtyn DN, Scharenberg AM, Wagtmann N, Rajagopalan S, Berrada K, Yi T, Kinet JP, Long EO (1996) Recruitment of tyrosine phosphatase HCP by the killer cell inhibitor receptor. Immunity 4:77–85

  22. Caligiuri MA (2008) Human natural killer cells. Blood 112:461–469

  23. Cany J, Van Der Waart AB, Spanholtz J, Tordoir M, Jansen JH, Van Der Voort R, Schaap NM, Dolstra H (2015) Combined IL-15 and IL-12 drives the generation of CD34(+)-derived natural killer cells with superior maturation and alloreactivity potential following adoptive transfer. Oncoimmunology 4:e1017701

  24. Carotta S (2016) Targeting NK cells for anticancer immunotherapy: clinical and preclinical approaches. Front Immunol 7:152

  25. Castriconi R, Daga A, Dondero A, Zona G, Poliani PL, Melotti A, Griffero F, Marubbi D, Spaziante R, Bellora F, Moretta L, Moretta A, Corte G, Bottino C (2009) NK cells recognize and kill human glioblastoma cells with stem cell-like properties. J Immunol 182:3530–3539

  26. Chang ZL, Chen YY (2017) CARs: synthetic immunoreceptors for cancer therapy and beyond. Trends Mol Med 23:430–450

  27. Chen J, Mckay RM, Parada LF (2012) Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell 149:36–47

  28. Childs RW, Carlsten M (2015) Therapeutic approaches to enhance natural killer cell cytotoxicity against cancer: the force awakens. Nat Rev Drug Discov 14:487–498

  29. Chiossone L, Vienne M, Kerdiles YM, Vivier E (2017) Natural killer cell immunotherapies against cancer: checkpoint inhibitors and more. Semin Immunol 31:55–63

  30. Chiossone L, Dumas PY, Vienne M, Vivier E (2018) Natural killer cells and other innate lymphoid cells in cancer. Nat Rev Immunol 18:671–688

  31. Cho YJ, Lee HH, Kang H, Cho H (2018) Cytokine-modulated natural killer cells differentially regulate the activity of the hepatitis C virus. Int J Mol Sci 19:2771

  32. Choi I, Yoon SR, Park SY, Kim H, Jung SJ, Jang YJ, Kang M, Yeom YI, Lee JL, Kim DY, Lee YS, Kang YA, Jeon M, Seol M, Lee JH, Lee JH, Kim HJ, Yun SC, Lee KH (2014) Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. Biol Blood Marrow Transplant 20:696–704

  33. Chretien AS, Le Roy A, Vey N, Prebet T, Blaise D, Fauriat C, Olive D (2014) Cancer-induced alterations of NK-mediated target recognition: current and investigational pharmacological strategies aiming at restoring NK-mediated anti-tumor activity. Front Immunol 5:122

  34. Cichocki F, Valamehr B, Bjordahl R, Zhang B, Rezner B, Rogers P, Gaidarova S, Moreno S, Tuininga K, Dougherty P, Mccullar V, Howard P, Sarhan D, Taras E, Schlums H, Abbot S, Shoemaker D, Bryceson YT, Blazar BR, Wolchko S, Cooley S, Miller JS (2017) GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. Cancer Res 77:5664–5675

  35. Cooley S, Parham P, Miller JS (2018) Strategies to activate NK cells to prevent relapse and induce remission following hematopoietic stem cell transplantation. Blood 131:1053–1062

  36. Da Silva IP, Gallois A, Jimenez-Baranda S, Khan S, Anderson AC, Kuchroo VK, Osman I, Bhardwaj N (2014) Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunol Res 2:410–422

  37. Das A, Long EO (2010) Lytic granule polarization, rather than degranulation, is the preferred target of inhibitory receptors in NK cells. J Immunol 185:4698–4704

  38. Delconte RB, Kolesnik TB, Dagley LF, Rautela J, Shi W, Putz EM, Stannard K, Zhang JG, Teh C, Firth M, Ushiki T, Andoniou CE, Degli-Esposti MA, Sharp PP, Sanvitale CE, Infusini G, Liau NP, Linossi EM, Burns CJ, Carotta S, Gray DH, Seillet C, Hutchinson DS, Belz GT, Webb AI, Alexander WS, Li SS, Bullock AN, Babon JJ, Smyth MJ, Nicholson SE, Huntington ND (2016) CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nat Immunol 17:816–824

  39. Della Chiesa M, Pesce S, Muccio L, Carlomagno S, Sivori S, Moretta A, Marcenaro E (2016) Features of memory-like and PD-1(+) human NK cell subsets. Front Immunol 7:351

  40. Domogala A, Madrigal JA, Saudemont A (2015) Natural killer cell immunotherapy: from bench to bedside. Front Immunol 6:264

  41. Dong Z, Cruz-Munoz ME, Zhong MC, Chen R, Latour S, Veillette A (2009) Essential function for SAP family adaptors in the surveillance of hematopoietic cells by natural killer cells. Nat Immunol 10:973–980

  42. Dong Z, Davidson D, Perez-Quintero LA, Kurosaki T, Swat W, Veillette A (2012) The adaptor SAP controls NK cell activation by regulating the enzymes Vav-1 and SHIP-1 and by enhancing conjugates with target cells. Immunity 36:974–985

  43. Dotti G, Gottschalk S, Savoldo B, Brenner MK (2014) Design and development of therapies using chimeric antigen receptor-expressing T cells. Immunol Rev 257:107–126

  44. Dubois S, Mariner J, Waldmann TA, Tagaya Y (2002) IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells. Immunity 17:537–547

  45. Dubois S, Patel HJ, Zhang M, Waldmann TA, Muller JR (2008) Preassociation of IL-15 with IL-15R alpha-IgG1-Fc enhances its activity on proliferation of NK and CD8+/CD44 high T cells and its antitumor action. J Immunol 180:2099–2106

  46. Dubois S, Conlon KC, Muller JR, Hsu-Albert J, Beltran N, Bryant BR, Waldmann TA (2017) IL15 infusion of cancer patients expands the subpopulation of cytotoxic CD56(bright) NK cells and increases NK-cell cytokine release capabilities. Cancer Immunol Res 5:929–938

  47. Eagle RA, Trowsdale J (2007) Promiscuity and the single receptor: NKG2D. Nat Rev Immunol 7:737–744

  48. Fang F, Xiao W, Tian Z (2017) NK cell-based immunotherapy for cancer. Semin Immunol 31:37–54

  49. Fauriat C, Just-Landi S, Mallet F, Arnoulet C, Sainty D, Olive D, Costello RT (2007) Deficient expression of NCR in NK cells from acute myeloid leukemia: evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction. Blood 109:323–330

  50. Filley AC, Henriquez M, Dey M (2018) CART immunotherapy: development, success, and translation to malignant gliomas and other solid tumors. Front Oncol 8:453

  51. Folgiero V, Cifaldi L, Li Pira G, Goffredo BM, Vinti L, Locatelli F (2015) TIM-3/Gal-9 interaction induces IFNgamma-dependent IDO1 expression in acute myeloid leukemia blast cells. J Hematol Oncol 8:36

  52. Gallois A, Silva I, Osman I, Bhardwaj N (2014) Reversal of natural killer cell exhaustion by TIM-3 blockade. Oncoimmunology 3:e946365

  53. Georgiadis C, Preece R, Nickolay L, Etuk A, Petrova A, Ladon D, Danyi A, Humphryes-Kirilov N, Ajetunmobi A, Kim D, Kim JS, Qasim W (2018) Long terminal repeat CRISPR-CAR-coupled “Universal” T cells mediate potent anti-leukemic effects. Mol Ther 26:1215–1227

  54. Ghasemi R, Lazear E, Wang X, Arefanian S, Zheleznyak A, Carreno BM, Higashikubo R, Gelman AE, Kreisel D, Fremont DH, Krupnick AS (2016) Selective targeting of IL-2 to NKG2D bearing cells for improved immunotherapy. Nat Commun 7:12878

  55. Gilfillan S, Chan CJ, Cella M, Haynes NM, Rapaport AS, Boles KS, Andrews DM, Smyth MJ, Colonna M (2008) DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors. J Exp Med 205:2965–2973

  56. Gillard-Bocquet M, Caer C, Cagnard N, Crozet L, Perez M, Fridman WH, Sautes-Fridman C, Cremer I (2013) Lung tumor microenvironment induces specific gene expression signature in intratumoral NK cells. Front Immunol 4:19

  57. Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, Knoblaugh S, Cado D, Greenberg NM, Raulet DH (2008) NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 28:571–580

  58. Guillerey C, Huntington ND, Smyth MJ (2016) Targeting natural killer cells in cancer immunotherapy. Nat Immunol 17:1025–1036

  59. Guo Y, Luan L, Rabacal W, Bohannon JK, Fensterheim BA, Hernandez A, Sherwood ER (2015) IL-15 superagonist-mediated immunotoxicity: role of NK cells and IFN-gamma. J Immunol 195:2353–2364

  60. Gust J, Taraseviciute A, Turtle CJ (2018) Neurotoxicity associated with CD19-targeted CAR-T cell therapies. CNS Drugs 32:1091–1101

  61. Halfteck GG, Elboim M, Gur C, Achdout H, Ghadially H, Mandelboim O (2009) Enhanced in vivo growth of lymphoma tumors in the absence of the NK-activating receptor NKp46/NCR1. J Immunol 182:2221–2230

  62. Hartmann J, Schussler-Lenz M, Bondanza A, Buchholz CJ (2017) Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med 9:1183–1197

  63. Holmes TD, El-Sherbiny YM, Davison A, Clough SL, Blair GE, Cook GP (2011) A human NK cell activation/inhibition threshold allows small changes in the target cell surface phenotype to dramatically alter susceptibility to NK cells. J Immunol 186:1538–1545

  64. Hsu J, Hodgins JJ, Marathe M, Nicolai CJ, Bourgeois-Daigneault MC, Trevino TN, Azimi CS, Scheer AK, Randolph HE, Thompson TW, Zhang L, Iannello A, Mathur N, Jardine KE, Kirn GA, Bell JC, Mcburney MW, Raulet DH, Ardolino M (2018) Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J Clin Invest 128:4654–4668

  65. Huang F, Gu H (2008) Negative regulation of lymphocyte development and function by the Cbl family of proteins. Immunol Rev 224:229–238

  66. Huang R, Zhang D, Li F, Xiao Z, Wu M, Shi D, Xiang P, Bao Z (2017) Loss of Fas expression and high expression of HLA-E promoting the immune escape of early colorectal cancer cells. Oncol Lett 13:3379–3386

  67. Hung AL, Maxwell R, Theodros D, Belcaid Z, Mathios D, Luksik AS, Kim E, Wu A, Xia Y, Garzon-Muvdi T, Jackson C, Ye X, Tyler B, Selby M, Korman A, Barnhart B, Park SM, Youn JI, Chowdhury T, Park CK, Brem H, Pardoll DM, Lim M (2018) TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. Oncoimmunology 7:e1466769

  68. Imamura M, Shook D, Kamiya T, Shimasaki N, Chai SM, Coustan-Smith E, Imai C, Campana D (2014) Autonomous growth and increased cytotoxicity of natural killer cells expressing membrane-bound interleukin-15. Blood 124:1081–1088

  69. Ito S, Bollard CM, Carlsten M, Melenhorst JJ, Biancotto A, Wang E, Chen J, Kotliarov Y, Cheung F, Xie Z, Marincola F, Tanimoto K, Battiwalla M, Olnes MJ, Perl S, Schum P, Hughes TE, Keyvanfar K, Hensel N, Muranski P, Young NS, Barrett AJ (2014) Ultra-low dose interleukin-2 promotes immune-modulating function of regulatory T cells and natural killer cells in healthy volunteers. Mol Ther 22:1388–1395

  70. Jie HB, Schuler PJ, Lee SC, Srivastava RM, Argiris A, Ferrone S, Whiteside TL, Ferris RL (2015) CTLA-4(+) regulatory T cells increased in cetuximab-treated head and neck cancer patients suppress NK cell cytotoxicity and correlate with poor prognosis. Cancer Res 75:2200–2210

  71. Joshi RP, Schmidt AM, Das J, Pytel D, Riese MJ, Lester M, Diehl JA, Behrens EM, Kambayashi T, Koretzky GA (2013) The zeta isoform of diacylglycerol kinase plays a predominant role in regulatory T cell development and TCR-mediated ras signaling. Sci Signal 6:ra102

  72. Karre K, Ljunggren HG, Piontek G, Kiessling R (1986) Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319:675–678

  73. Kaur P, Asea A (2012) Radiation-induced effects and the immune system in cancer. Front Oncol 2:191

  74. Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, White DE, Wunderlich JR, Canevari S, Rogers-Freezer L, Chen CC, Yang JC, Rosenberg SA, Hwu P (2006) A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res 12:6106–6115

  75. Kiessling R, Klein E, Wigzell H (1975) “Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur J Immunol 5:112–117

  76. Kim HS (2015) A multifaceted approach targeting NK cells for better treatment of cancer: focus on hematological malignancies. Blood Res 50:189–191

  77. Kim N, Kim HS (2018) Targeting checkpoint receptors and molecules for therapeutic modulation of natural killer cells. Front Immunol 9:2041

  78. Kim HS, Long EO (2012) Complementary phosphorylation sites in the adaptor protein SLP-76 promote synergistic activation of natural killer cells. Sci Signal 5:49

  79. Kim S, Poursine-Laurent J, Truscott SM, Lybarger L, Song YJ, Yang L, French AR, Sunwoo JB, Lemieux S, Hansen TH, Yokoyama WM (2005) Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436:709–713

  80. Kim HS, Das A, Gross CC, Bryceson YT, Long EO (2010) Synergistic signals for natural cytotoxicity are required to overcome inhibition by c-Cbl ubiquitin ligase. Immunity 32:175–186

  81. Kim PS, Kwilas AR, Xu W, Alter S, Jeng EK, Wong HC, Schlom J, Hodge JW (2016) IL-15 superagonist/IL-15RalphaSushi-Fc fusion complex (IL-15SA/IL-15RalphaSu-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8 + T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas. Oncotarget 7:16130–16145

  82. Kloss S, Oberschmidt O, Morgan M, Dahlke J, Arseniev L, Huppert V, Granzin M, Gardlowski T, Matthies N, Soltenborn S, Schambach A, Koehl U (2017) Optimization of human NK cell manufacturing: fully automated separation, improved ex vivo expansion using IL-21 with autologous feeder cells, and generation of anti-CD123-CAR-expressing effector cells. Hum Gene Ther 28:897–913

  83. Kohrt HE, Thielens A, Marabelle A, Sagiv-Barfi I, Sola C, Chanuc F, Fuseri N, Bonnafous C, Czerwinski D, Rajapaksa A, Waller E, Ugolini S, Vivier E, Romagne F, Levy R, Blery M, Andre P (2014) Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies. Blood 123:678–686

  84. Koka R, Burkett P, Chien M, Chai S, Boone DL, Ma A (2004) Cutting edge: murine dendritic cells require IL-15R alpha to prime NK cells. J Immunol 173:3594–3598

  85. Komita H, Koido S, Hayashi K, Kan S, Ito M, Kamata Y, Suzuki M, Homma S (2015) Expression of immune checkpoint molecules of T cell immunoglobulin and mucin protein 3/galectin-9 for NK cell suppression in human gastrointestinal stromal tumors. Oncol Rep 34:2099–2105

  86. Kucan Brlic P, Lenac Rovis T, Cinamon G, Tsukerman P, Mandelboim O, Jonjic S (2018) Targeting PVR (CD155) and its receptors in anti-tumor therapy. Cell Mol Immunol 16:40–52

  87. Kwon HJ, Kwon SJ, Lee H, Park HR, Choi GE, Kang SW, Kwon SW, Kim N, Lee SY, Ryu S, Kim SC, Kim HS (2015) NK cell function triggered by multiple activating receptors is negatively regulated by glycogen synthase kinase-3beta. Cell Signal 27:1731–1741

  88. Kwon HJ, Choi GE, Ryu S, Kwon SJ, Kim SC, Booth C, Nichols KE, Kim HS (2016) Stepwise phosphorylation of p65 promotes NF-kappaB activation and NK cell responses during target cell recognition. Nat Commun 7:11686

  89. Kwon HJ, Kim N, Kim HS (2017) Molecular checkpoints controlling natural killer cell activation and their modulation for cancer immunotherapy. Exp Mol Med 49:e311

  90. Lang S, Vujanovic NL, Wollenberg B, Whiteside TL (1998) Absence of B7.1-CD28/CTLA-4-mediated co-stimulation in human NK cells. Eur J Immunol 28:780–786

  91. Lanier LL (2005) NK cell recognition. Annu Rev Immunol 23:225–274

  92. Lanier LL (2008) Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 9:495–502

  93. Lanuza PM, Vigueras A, Olivan S, Prats AC, Costas S, Llamazares G, Sanchez-Martinez D, Ayuso JM, Fernandez L, Ochoa I, Pardo J (2018) Activated human primary NK cells efficiently kill colorectal cancer cells in 3D spheroid cultures irrespectively of the level of PD-L1 expression. Oncoimmunology 7:e1395123

  94. Lehmann D, Spanholtz J, Sturtzel C, Tordoir M, Schlechta B, Groenewegen D, Hofer E (2014) IL-12 directs further maturation of ex vivo differentiated NK cells with improved therapeutic potential. PLoS ONE 9:e87131

  95. Leong JW, Chase JM, Romee R, Schneider SE, Sullivan RP, Cooper MA, Fehniger TA (2014) 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 20:463–473

  96. Li Y, Hermanson DL, Moriarity BS, Kaufman DS (2018) Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell 23(181–192):e5

  97. Liu CH, Machado FS, Guo R, Nichols KE, Burks AW, Aliberti JC, Zhong XP (2007) Diacylglycerol kinase zeta regulates microbial recognition and host resistance to Toxoplasma gondii. J Exp Med 204:781–792

  98. Liu D, Peterson ME, Long EO (2012) The adaptor protein Crk controls activation and inhibition of natural killer cells. Immunity 36:600–611

  99. Liu X, Zhang Y, Cheng C, Cheng AW, Zhang X, Li N, Xia C, Wei X, Liu X, Wang H (2017) CRISPR-Cas9-mediated multiplex gene editing in CAR-T cells. Cell Res 27:154–157

  100. Liu E, Tong Y, Dotti G, Shaim H, Savoldo B, Mukherjee M, Orange J, Wan X, Lu X, Reynolds A, Gagea M, Banerjee P, Cai R, Bdaiwi MH, Basar R, Muftuoglu M, Li L, Marin D, Wierda W, Keating M, Champlin R, Shpall E, Rezvani K (2018) Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia 32:520–531

  101. Long EO (2008) Negative signaling by inhibitory receptors: the NK cell paradigm. Immunol Rev 224:70–84

  102. Long EO, Kim HS, Liu D, Peterson ME, Rajagopalan S (2013) Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol 31:227–258

  103. Lopez-Soto A, Gonzalez S, Smyth MJ, Galluzzi L (2017) Control of metastasis by NK cells. Cancer Cell 32:135–154

  104. Lusty E, Poznanski SM, Kwofie K, Mandur TS, Lee DA, Richards CD, Ashkar AA (2017) IL-18/IL-15/IL-12 synergy induces elevated and prolonged IFN-gamma production by ex vivo expanded NK cells which is not due to enhanced STAT4 activation. Mol Immunol 88:138–147

  105. Magee JA, Piskounova E, Morrison SJ (2012) Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 21:283–296

  106. Malmberg KJ, Carlsten M, Bjorklund A, Sohlberg E, Bryceson YT, Ljunggren HG (2017) Natural killer cell-mediated immunosurveillance of human cancer. Semin Immunol 31:20–29

  107. Marcais A, Viel S, Grau M, Henry T, Marvel J, Walzer T (2013) Regulation of mouse NK cell development and function by cytokines. Front Immunol 4:450

  108. Mcwilliams EM, Mele JM, Cheney C, Timmerman EA, Fiazuddin F, Strattan EJ, Mo X, Byrd JC, Muthusamy N, Awan FT (2016) Therapeutic CD94/NKG2A blockade improves natural killer cell dysfunction in chronic lymphocytic leukemia. Oncoimmunology 5:e1226720

  109. Mentlik James A, Cohen AD, Campbell KS (2013) Combination immune therapies to enhance anti-tumor responses by NK cells. Front Immunol 4:481

  110. Mirzaei HR, Rodriguez A, Shepphird J, Brown CE, Badie B (2017) Chimeric antigen receptors T cell therapy in solid tumor: challenges and clinical applications. Front Immunol 8:1850

  111. Moretta A (2002) Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol 2:957–964

  112. Moretta L, Moretta A (2004) Unravelling natural killer cell function: triggering and inhibitory human NK receptors. EMBO J 23:255–259

  113. Morvan MG, Lanier LL (2016) NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer 16:7–19

  114. O’rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, Martinez-Lage M, Brem S, Maloney E, Shen A, Isaacs R, Mohan S, Plesa G, Lacey SF, Navenot JM, Zheng Z, Levine BL, Okada H, June CH, Brogdon JL, Maus MV (2017) A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med 9:eaaa0984

  115. Olcese L, Lang P, Vely F, Cambiaggi A, Marguet D, Blery M, Hippen KL, Biassoni R, Moretta A, Moretta L, Cambier JC, Vivier E (1996) Human and mouse killer-cell inhibitory receptors recruit PTP1C and PTP1D protein tyrosine phosphatases. J Immunol 156:4531–4534

  116. Paidipally P, Tripathi D, Van A, Radhakrishnan RK, Dhiman R, Venkatasubramanian S, Devalraju KP, Tvinnereim AR, Valluri VL, Vankayalapati R (2018) Interleukin-21 regulates natural killer cell responses during mycobacterium tuberculosis infection. J Infect Dis 217:1323–1333

  117. Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP, Cronin SJ, Nitsch R, Schultz-Fademrecht C, Eickhoff J, Menninger S, Unger A, Torka R, Gruber T, Hinterleitner R, Baier G, Wolf D, Ullrich A, Klebl BM, Penninger JM (2014) The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507:508–512

  118. Parameswaran R, Ramakrishnan P, Moreton SA, Xia Z, Hou Y, Lee DA, Gupta K, Delima M, Beck RC, Wald DN (2016) Repression of GSK3 restores NK cell cytotoxicity in AML patients. Nat Commun 7:11154

  119. Park JR, Digiusto DL, Slovak M, Wright C, Naranjo A, Wagner J, Meechoovet HB, Bautista C, Chang WC, Ostberg JR, Jensen MC (2007) Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther 15:825–833

  120. Parolini S, Bottino C, Falco M, Augugliaro R, Giliani S, Franceschini R, Ochs HD, Wolf H, Bonnefoy JY, Biassoni R, Moretta L, Notarangelo LD, Moretta A (2000) X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells. J Exp Med 192:337–346

  121. Perez-Martinez A, Fernandez L, Valentin J, Martinez-Romera I, Corral MD, Ramirez M, Abad L, Santamaria S, Gonzalez-Vicent M, Sirvent S, Sevilla J, Vicario JL, De Prada I, Diaz MA (2015) A phase I/II trial of interleukin-15-stimulated natural killer cell infusion after haplo-identical stem cell transplantation for pediatric refractory solid tumors. Cytotherapy 17:1594–1603

  122. Pesce S, Greppi M, Tabellini G, Rampinelli F, Parolini S, Olive D, Moretta L, Moretta A, Marcenaro E (2016) Identification of a subset of human natural killer cells expressing high levels of programmed death 1: a phenotypic and functional characterization. J Allergy Clin Immunol 139:335–346

  123. Pietra G, Manzini C, Vitale M, Balsamo M, Ognio E, Boitano M, Queirolo P, Moretta L, Mingari MC (2009) Natural killer cells kill human melanoma cells with characteristics of cancer stem cells. Int Immunol 21:793–801

  124. Pittari G, Filippini P, Gentilcore G, Grivel JC, Rutella S (2015) Revving up natural killer cells and cytokine-induced killer cells against hematological malignancies. Front Immunol 6:230

  125. Platonova S, Cherfils-Vicini J, Damotte D, Crozet L, Vieillard V, Validire P, Andre P, Dieu-Nosjean MC, Alifano M, Regnard JF, Fridman WH, Sautes-Fridman C, Cremer I (2011) Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Res 71:5412–5422

  126. Pross HF, Jondal M (1975) Cytotoxic lymphocytes from normal donors. A functional marker of human non-T lymphocytes. Clin Exp Immunol 21:226–235

  127. Raulet DH, Guerra N (2009) Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat Rev Immunol 9:568–580

  128. Raulet DH, Gasser S, Gowen BG, Deng W, Jung H (2013) Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol 31:413–441

  129. Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y (2017) Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin Cancer Res 23:2255–2266

  130. Rezvani K, Rouce RH (2015) The application of natural killer cell immunotherapy for the treatment of cancer. Front Immunol 6:578

  131. Rezvani K, Rouce R, Liu E, Shpall E (2017) Engineering Natural killer cells for cancer immunotherapy. Mol Ther 25:1769–1781

  132. Romagne F, Vivier E (2011) Natural killer cell-based therapies. F1000 Med Rep 3:9

  133. Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E, Vetto JT, Seipp CA, Simpson C, Reichert CM (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313:1485–1492

  134. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295:2097–2100

  135. Ruggeri L, Urbani E, Andre P, Mancusi A, Tosti A, Topini F, Blery M, Animobono L, Romagne F, Wagtmann N, Velardi A (2016) Effects of anti-NKG2A antibody administration on leukemia and normal hematopoietic cells. Haematologica 101:626–633

  136. Saunders PM, Vivian JP, O’connor GM, Sullivan LC, Pymm P, Rossjohn J, Brooks AG (2015) A bird’s eye view of NK cell receptor interactions with their MHC class I ligands. Immunol Rev 267:148–166

  137. Schmidt AM, Zou T, Joshi RP, Leichner TM, Pimentel MA, Sommers CL, Kambayashi T (2013) Diacylglycerol kinase zeta limits the generation of natural regulatory T cells. Sci Signal 6:101

  138. Seo H, Jeon I, Kim BS, Park M, Bae EA, Song B, Koh CH, Shin KS, Kim IK, Choi K, Oh T, Min J, Min BS, Han YD, Kang SJ, Shin SJ, Chung Y, Kang CY (2017) IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours. Nat Commun 8:15776

  139. Shah NN, Baird K, Delbrook CP, Fleisher TA, Kohler ME, Rampertaap S, Lemberg K, Hurley CK, Kleiner DE, Merchant MS, Pittaluga S, Sabatino M, Stroncek DF, Wayne AS, Zhang H, Fry TJ, Mackall CL (2015) Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation. Blood 125:784–792

  140. Sim GC, Liu C, Wang E, Liu H, Creasy C, Dai Z, Overwijk WW, Roszik J, Marincola F, Hwu P, Grimm E, Radvanyi L (2016) IL2 variant circumvents ICOS + regulatory T-cell expansion and promotes NK cell activation. Cancer Immunol Res 4:983–994

  141. Skak K, Frederiksen KS, Lundsgaard D (2008) Interleukin-21 activates human natural killer cells and modulates their surface receptor expression. Immunology 123:575–583

  142. Stebbins CC, Watzl C, Billadeau DD, Leibson PJ, Burshtyn DN, Long EO (2003) Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity. Mol Cell Biol 23:6291–6299

  143. Stojanovic A, Fiegler N, Brunner-Weinzierl M, Cerwenka A (2014) CTLA-4 is expressed by activated mouse NK cells and inhibits NK Cell IFN-gamma production in response to mature dendritic cells. J Immunol 192:4184–4191

  144. Suck G, Odendahl M, Nowakowska P, Seidl C, Wels WS, Klingemann HG, Tonn T (2016) NK-92: an ‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother 65:485–492

  145. Sun C, Xu J, Huang Q, Huang M, Wen H, Zhang C, Wang J, Song J, Zheng M, Sun H, Wei H, Xiao W, Sun R, Tian Z (2017) High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer. Oncoimmunology 6:e1264562

  146. Szmania S, Lapteva N, Garg T, Greenway A, Lingo J, Nair B, Stone K, Woods E, Khan J, Stivers J, Panozzo S, Campana D, Bellamy WT, Robbins M, Epstein J, Yaccoby S, Waheed S, Gee A, Cottler-Fox M, Rooney C, Barlogie B, Van Rhee F (2015) Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. J Immunother 38:24–36

  147. Tabellini G, Benassi M, Marcenaro E, Coltrini D, Patrizi O, Ricotta D, Rampinelli F, Moretta A, Parolini S (2014) Primitive neuroectodermal tumor in an ovarian cystic teratoma: natural killer and neuroblastoma cell analysis. Case Rep Oncol 7:70–78

  148. Takeda K, Tsutsui H, Yoshimoto T, Adachi O, Yoshida N, Kishimoto T, Okamura H, Nakanishi K, Akira S (1998) Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity 8:383–390

  149. Tallerico R, Cristiani CM, Staaf E, Garofalo C, Sottile R, Capone M, Pico De Coana Y, Madonna G, Palella E, Wolodarski M, Carannante V, Mallardo D, Simeone E, Grimaldi AM, Johansson S, Frumento P, Gulletta E, Anichini A, Colucci F, Ciliberto G, Kiessling R, Karre K, Ascierto PA, Carbone E (2017) IL-15, TIM-3 and NK cells subsets predict responsiveness to anti-CTLA-4 treatment in melanoma patients. Oncoimmunology 6:e1261242

  150. Tang X, Yang L, Li Z, Nalin AP, Dai H, Xu T, Yin J, You F, Zhu M, Shen W, Chen G, Zhu X, Wu D, Yu J (2018) First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. Am J Cancer Res 8:1083–1089

  151. Thielens A, Vivier E, Romagne F (2012) NK cell MHC class I specific receptors (KIR): from biology to clinical intervention. Curr Opin Immunol 24:239–245

  152. Topfer K, Cartellieri M, Michen S, Wiedemuth R, Muller N, Lindemann D, Bachmann M, Fussel M, Schackert G, Temme A (2015) DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. J Immunol 194:3201–3212

  153. Upshaw JL, Arneson LN, Schoon RA, Dick CJ, Billadeau DD, Leibson PJ (2006) NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells. Nat Immunol 7:524–532

  154. Van Audenaerde JRM, De Waele J, Marcq E, Van Loenhout J, Lion E, Van Den Bergh JMJ, Jesenofsky R, Masamune A, Roeyen G, Pauwels P, Lardon F, Peeters M, Smits ELJ (2017) Interleukin-15 stimulates natural killer cell-mediated killing of both human pancreatic cancer and stellate cells. Oncotarget 8:56968–56979

  155. Veluchamy JP, Kok N, Van Der Vliet HJ, Verheul HMW, De Gruijl TD, Spanholtz J (2017) The rise of allogeneic natural killer cells as a platform for cancer immunotherapy: recent innovations and future developments. Front Immunol 8:631

  156. Vey N, Karlin L, Sadot-Lebouvier S, Broussais F, Berton-Rigaud D, Rey J, Charbonnier A, Marie D, Andre P, Paturel C, Zerbib R, Bennouna J, Salles G, Goncalves A (2018) A phase 1 study of lirilumab (antibody against killer immunoglobulin-like receptor antibody KIR2D; IPH2102) in patients with solid tumors and hematologic malignancies. Oncotarget 9:17675–17688

  157. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S (2008) Functions of natural killer cells. Nat Immunol 9:503–510

  158. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, Yokoyama WM, Ugolini S (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331:44–49

  159. Vivier E, Ugolini S, Blaise D, Chabannon C, Brossay L (2012) Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol 12:239–252

  160. Wang Z, Zhu J, Gu H, Yuan Y, Zhang B, Zhu D, Zhou J, Zhu Y, Chen W (2015) The clinical significance of abnormal Tim-3 expression on NK cells from patients with gastric cancer. Immunol Invest 44:578–589

  161. West WH, Tauer KW, Yannelli JR, Marshall GD, Orr DW, Thurman GB, Oldham RK (1987) Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 316:898–905

  162. Wu Z, Xu Y (2010) IL-15R alpha-IgG1-Fc enhances IL-2 and IL-15 anti-tumor action through NK and CD8 + T cells proliferation and activation. J Mol Cell Biol 2:217–222

  163. Xiong W, Chen Y, Kang X, Chen Z, Zheng P, Hsu YH, Jang JH, Qin L, Liu H, Dotti G, Liu D (2018) Immunological synapse predicts effectiveness of chimeric antigen receptor cells. Mol Ther 26:963–975

  164. Xu L, Huang Y, Tan L, Yu W, Chen D, Lu C, He J, Wu G, Liu X, Zhang Y (2015) Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma. Int Immunopharmacol 29:635–641

  165. Yang E, Singh BK, Paustian AM, Kambayashi T (2016) Diacylglycerol kinase zeta is a target to enhance NK cell function. J Immunol 197:934–941

  166. Yong AS, Keyvanfar K, Hensel N, Eniafe R, Savani BN, Berg M, Lundqvist A, Adams S, Sloand EM, Goldman JM, Childs R, Barrett AJ (2009) Primitive quiescent CD34+ cells in chronic myeloid leukemia are targeted by in vitro expanded natural killer cells, which are functionally enhanced by bortezomib. Blood 113:875–882

  167. Yoshimoto T, Takeda K, Tanaka T, Ohkusu K, Kashiwamura S, Okamura H, Akira S, Nakanishi K (1998) IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production. J Immunol 161:3400–3407

  168. Zeijlemaker W, Gratama JW, Schuurhuis GJ (2014) Tumor heterogeneity makes AML a “moving target” for detection of residual disease. Cytometry B 86:3–14

  169. Zhang Z, Wu N, Lu Y, Davidson D, Colonna M, Veillette A (2015) DNAM-1 controls NK cell activation via an ITT-like motif. J Exp Med 212:2165–2182

  170. Zhang C, Oberoi P, Oelsner S, Waldmann A, Lindner A, Tonn T, Wels WS (2017) Chimeric antigen receptor-engineered NK-92 cells: an off-the-shelf cellular therapeutic for targeted elimination of cancer cells and induction of protective antitumor immunity. Front Immunol 8:533

  171. Zhang Q, Bi J, Zheng X, Chen Y, Wang H, Wu W, Wang Z, Wu Q, Peng H, Wei H, Sun R, Tian Z (2018a) Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol 19:723–732

  172. Zhang W, Feng H, Chen Q, Lu X, Ge J (2018b) The functional potency of natural killer cells in response to IL-2/IL-15/IL-21 stimulation is limited by a concurrent upregulation of Tim-3 in bladder cancer. Exp Cell Res 372:92–98

  173. Zingoni A, Fionda C, Borrelli C, Cippitelli M, Santoni A, Soriani A (2017) Natural killer cell response to chemotherapy-stressed cancer cells: role in tumor immunosurveillance. Front Immunol 8:1194

  174. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G (2008) Immunological aspects of cancer chemotherapy. Nat Rev Immunol 8:59–73

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Acknowledgements

This study was supported by a grant from the Korea Health Technology Research and Development Project of the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HI15C0972, to N.K.); a grant from the National Research Foundation of Korea (2019R1A2C2006475 to H.S.K.); a grant by the Intelligent Synthetic Biology Center of the Global Frontier Project (2013-0073185, to H.S.K.); and a MRC Grant (2018R1A5A2020732, to H.S.K.) funded by the Korean government (MSIT).

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Kim, N., Lee, H.H., Lee, H. et al. Natural killer cells as a promising therapeutic target for cancer immunotherapy. Arch. Pharm. Res. 42, 591–606 (2019). https://doi.org/10.1007/s12272-019-01143-y

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Keywords

  • Natural killer cells
  • Inhibitory receptors
  • Activating receptors
  • Checkpoint inhibition
  • Cancer immunotherapy