DOI QR코드

DOI QR Code

Harnessing NK cells for cancer immunotherapy: immune checkpoint receptors and chimeric antigen receptors

  • Kim, Nayoung (Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Lee, Dong-Hee (Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Choi, Woo Seon (Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Yi, Eunbi (Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, HyoJeong (Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Jung Min (Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Jin, Hyung-Seung (Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Hun Sik (Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2020.09.29
  • Accepted : 2020.12.03
  • Published : 2021.01.31

Abstract

Natural killer (NK) cells, key antitumor effectors of the innate immune system, are endowed with the unique ability to spontaneously eliminate cells undergoing a neoplastic transformation. Given their broad reactivity against diverse types of cancer and close association with cancer prognosis, NK cells have gained considerable attention as a promising therapeutic target for cancer immunotherapy. NK cell-based therapies have demonstrated favorable clinical efficacies in several hematological malignancies but limited success in solid tumors, thus highlighting the need to develop new therapeutic strategies to restore and optimize anti-tumor activity while preventing tumor immune escape. The current therapeutic modalities yielding encouraging results in clinical trials include the blockade of immune checkpoint receptors to overcome the immune-evasion mechanism used by tumors and the incorporation of tumor-directed chimeric antigen receptors to enhance NK cell anti-tumor specificity and activity. These observations, together with recent advances in the understanding of NK cell activation within the tumor microenvironment, will facilitate the optimal design of NK cell-based therapy against a broad range of cancers and, more desirably, refractory cancers.

Keywords

Acknowledgement

This study was supported by a grant from the National Research Foundation of Korea (2019R1A2C2006475) and an MRC grant (2018R1A5A2020732) funded by the Korean government (MSIT).

References

  1. Larkin J, Chiarion-Sileni V, Gonzalez R et al (2015) Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373, 23-34 https://doi.org/10.1056/NEJMoa1504030
  2. Ishida Y, Agata Y, Shibahara K and Honjo T (1992) Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11, 3887-3895 https://doi.org/10.1002/j.1460-2075.1992.tb05481.x
  3. Selvakumar A, Mohanraj BK, Eddy RL, Shows TB, White PC and Dupont B (1992) Genomic organization and chromosomal location of the human gene encoding the B-lymphocyte activation antigen B7. Immunogenetics 36, 175-181 https://doi.org/10.1007/BF00661094
  4. Karre K, Ljunggren HG, Piontek G and Kiessling R (1986) Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319, 675-678 https://doi.org/10.1038/319675a0
  5. Kim S, Poursine-Laurent J, Truscott SM et al (2005) Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436, 709-713 https://doi.org/10.1038/nature03847
  6. Kim S, Sunwoo JB, Yang L et al (2008) HLA alleles determine differences in human natural killer cell responsiveness and potency. Proc Natl Acad Sci U S A 105, 3053-3058 https://doi.org/10.1073/pnas.0712229105
  7. Djaoud Z and Parham P (2020) HLAs, TCRs, and KIRs, a triumvirate of human cell-mediated immunity. Annu Rev Biochem 89, 717-739 https://doi.org/10.1146/annurev-biochem-011520-102754
  8. Saunders PM, Vivian JP, O'Connor GM et al (2015) A bird's eye view of NK cell receptor interactions with their MHC class I ligands. Immunol Rev 267, 148-166 https://doi.org/10.1111/imr.12319
  9. Benson DM, Jr., Hofmeister CC, Padmanabhan S et al (2012) A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma. Blood 120, 4324-4333
  10. Vey N, Bourhis JH, Boissel N et al (2012) A phase 1 trial of the anti-inhibitory KIR mAb IPH2101 for AML in complete remission. Blood 120, 4317-4323
  11. Carlsten M, Korde N, Kotecha R et al (2016) Checkpoint inhibition of KIR2D with the monoclonal antibody IPH2101 induces contraction and hyporesponsiveness of NK cells in patients with myeloma. Clin Cancer Res 22, 5211-5222 https://doi.org/10.1158/1078-0432.CCR-16-1108
  12. Benson DM Jr, Cohen AD, Jagannath S et al (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 https://doi.org/10.1158/1078-0432.CCR-15-0304
  13. Kohrt HE, Thielens A, Marabelle A et al (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 https://doi.org/10.1182/blood-2013-08-519199
  14. Yalniz FF, Daver N, Rezvani K et al (2018) A pilot trial of Lirilumab with or without Azacitidine for patients with myelodysplastic syndrome. Clin Lymphoma Myeloma Leuk 18, 658-663 e652 https://doi.org/10.1016/j.clml.2018.06.011
  15. Binyamin L, Alpaugh RK, Hughes TL, Lutz CT, Campbell KS and Weiner LM (2008) Blocking NK cell inhibitory self-recognition promotes antibody-dependent cellular cytotoxicity in a model of anti-lymphoma therapy. J Immunol 180, 6392-6401 https://doi.org/10.4049/jimmunol.180.9.6392
  16. Bagot M, Porcu P, Marie-Cardine A et al (2019) IPH4102, a first-in-class anti-KIR3DL2 monoclonal antibody, in patients with relapsed or refractory cutaneous T-cell lymphoma: an international, first-in-human, open-label, phase 1 trial. Lancet Oncol 20, 1160-1170 https://doi.org/10.1016/s1470-2045(19)30320-1
  17. Ewen EM, Pahl JHW, Miller M, Watzl C and Cerwenka A (2018) KIR downregulation by IL-12/15/18 unleashes human NK cells from KIR/HLA-I inhibition and enhances killing of tumor cells. Eur J Immunol 48, 355-365 https://doi.org/10.1002/eji.201747128
  18. Shiroishi M, Tsumoto K, Amano K et al (2003) Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G. Proc Natl Acad Sci U S A 100, 8856-8861 https://doi.org/10.1073/pnas.1431057100
  19. Khan M, Arooj S and Wang H (2020) NK cell-based immune checkpoint inhibition. Front Immunol 11, 167 https://doi.org/10.3389/fimmu.2020.00167
  20. Scarabel L, Garziera M, Fortuna S, Asaro F, Toffoli G and Geremia S (2020) Soluble HLA-G expression levels and HLA-G/irinotecan association in metastatic colorectal cancer treated with irinotecan-based strategy. Sci Rep 10, 8773 https://doi.org/10.1038/s41598-020-65424-z
  21. Bertol BC, de Araujo JNG, Sadissou IA et al (2020) Plasma levels of soluble HLA-G and cytokines in papillary thyroid carcinoma before and after thyroidectomy. Int J Clin Pract 74, e13585
  22. Heidenreich S, Zu Eulenburg C, Hildebrandt Y et al (2012) Impact of the NK cell receptor LIR-1 (ILT-2/CD85j/LILRB1) on cytotoxicity against multiple myeloma. Clin Dev Immunol 2012, 652130
  23. Godal R, Bachanova V, Gleason M et al (2010) Natural killer cell killing of acute myelogenous leukemia and acute lymphoblastic leukemia blasts by killer cell immunoglobulin-like receptor-negative natural killer cells after NKG2A and LIR-1 blockade. Biol Blood Marrow Transplant 16, 612-621 https://doi.org/10.1016/j.bbmt.2010.01.019
  24. Ho GT, Celik AA, Huyton T et al (2020) NKG2A/CD94 is a new immune receptor for HLA-G and distinguishes amino acid differences in the HLA-G heavy chain. Int J Mol Sci 21, 4362 https://doi.org/10.3390/ijms21124362
  25. Burshtyn DN, Scharenberg AM, Wagtmann N et al (1996) Recruitment of tyrosine phosphatase HCP by the killer cell inhibitor receptor. Immunity 4, 77-85 https://doi.org/10.1016/S1074-7613(00)80300-3
  26. Olcese L, Lang P, Vely F et al (1996) Human and mouse killer-cell inhibitory receptors recruit PTP1C and PTP1D protein tyrosine phosphatases. J Immunol 156, 4531-4534
  27. Stebbins CC, Watzl C, Billadeau DD, Leibson PJ, Burshtyn DN and 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 https://doi.org/10.1128/MCB.23.17.6291-6299.2003
  28. Liu D, Peterson ME and Long EO (2012) The adaptor protein Crk controls activation and inhibition of natural killer cells. Immunity 36, 600-611 https://doi.org/10.1016/j.immuni.2012.03.007
  29. Long EO, Sik Kim H, Liu D, Peterson ME and Rajagopalan S (2013) Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol 31, 227-258 https://doi.org/10.1146/annurev-immunol-020711-075005
  30. Levy EM, Bianchini M, Von Euw EM et al (2008) Human leukocyte antigen-E protein is overexpressed in primary human colorectal cancer. Int J Oncol 32, 633-641
  31. Gooden M, Lampen M, Jordanova ES et al (2011) HLA-E expression by gynecological cancers restrains tumor-in-filtrating CD8(+) T lymphocytes. Proc Natl Acad Sci U S A 108, 10656-10661 https://doi.org/10.1073/pnas.1100354108
  32. Della Chiesa M, Pesce S, Muccio L et al (2016) Features of memory-like and PD-1(+) human NK cell subsets. Front Immunol 7, 351
  33. McWilliams EM, Mele JM, Cheney C et al (2016) Therapeutic CD94/NKG2A blockade improves natural killer cell dysfunction in chronic lymphocytic leukemia. Oncoimmunology 5, e1226720 https://doi.org/10.1080/2162402X.2016.1226720
  34. Chiossone L, Vienne M, Kerdiles YM and Vivier E (2017) Natural killer cell immunotherapies against cancer: checkpoint inhibitors and more. Semin Immunol 31, 55-63 https://doi.org/10.1016/j.smim.2017.08.003
  35. Burugu S, Dancsok AR and Nielsen TO (2018) Emerging targets in cancer immunotherapy. Semin Cancer Biol 52, 39-52
  36. Andre P, Denis C, Soulas C et al (2018) Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 175, 1731-1743 https://doi.org/10.1016/j.cell.2018.10.014
  37. van Montfoort N, Borst L, Korrer MJ et al (2018) NKG2A blockade potentiates CD8 T cell immunity induced by cancer vaccines. Cell 175, 1744-1755 https://doi.org/10.1016/j.cell.2018.10.028
  38. Schildberg FA, Klein SR, Freeman GJ and Sharpe AH (2016) Coinhibitory pathways in the B7-CD28 ligand-receptor family. Immunity 44, 955-972 https://doi.org/10.1016/j.immuni.2016.05.002
  39. Stojanovic A, Fiegler N, Brunner-Weinzierl M and 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 https://doi.org/10.4049/jimmunol.1302091
  40. Jie HB, Schuler PJ, Lee SC et al (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 https://doi.org/10.1158/0008-5472.CAN-14-2788
  41. Romano E, Kusio-Kobialka M, Foukas PG et al (2015) Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc Natl Acad Sci U S A 112, 6140-6145 https://doi.org/10.1073/pnas.1417320112
  42. Simpson TR, Li F, Montalvo-Ortiz W et al (2013) Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med 210, 1695-1710 https://doi.org/10.1084/jem.20130579
  43. Tallerico R, Cristiani CM, Staaf E et al (2017) IL-15, TIM-3 and NK cells subsets predict responsiveness to anti-CTLA-4 treatment in melanoma patients. Oncoimmunology 6, e1261242 https://doi.org/10.1080/2162402X.2016.1261242
  44. Jallad MN, Jurjus AR, Rahal EA and Abdelnoor AM (2020) Triple immunotherapy overcomes immune evasion by tumor in a melanoma mouse model. Front Oncol 10, 839 https://doi.org/10.3389/fonc.2020.00839
  45. Lang S, Vujanovic NL, Wollenberg B and Whiteside TL (1998) Absence of B7.1-CD28/CTLA-4-mediated co-stimulation in human NK cells. Eur J Immunol 28, 780-786 https://doi.org/10.1002/(SICI)1521-4141(199803)28:03<780::AID-IMMU780>3.0.CO;2-8
  46. Cook CH, Chen L, Wen J et al (2009) CD28/B7-mediated co-stimulation is critical for early control of murine cytomegalovirus infection. Viral Immunol 22, 91-103 https://doi.org/10.1089/vim.2008.0080
  47. Boussiotis VA, Chatterjee P and Li L (2014) Biochemical signaling of PD-1 on T cells and its functional implications. Cancer J 20, 265-271 https://doi.org/10.1097/ppo.0000000000000059
  48. Pesce S, Greppi M, Tabellini G et al (2017) 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 e333 https://doi.org/10.1016/j.jaci.2016.04.025
  49. Tabellini G, Benassi M, Marcenaro E et al (2014) Primitive neuroectodermal tumor in an ovarian cystic teratoma: natural killer and neuroblastoma cell analysis. Case Rep Oncol 7, 70-78 https://doi.org/10.1159/000357802
  50. Beldi-Ferchiou A, Lambert M, Dogniaux S et al (2016) PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma. Oncotarget 7, 72961-72977 https://doi.org/10.18632/oncotarget.12150
  51. Benson DM Jr, Bakan CE, Mishra A et al (2010) 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 116, 2286-2294
  52. Vari F, Arpon D, Keane C et al (2018) Immune evasion via PD-1/PD-L1 on NK cells and monocyte/macrophages is more prominent in Hodgkin lymphoma than DLBCL. Blood 131, 1809-1819 https://doi.org/10.1182/blood-2017-07-796342
  53. Hsu J, Hodgins JJ, Marathe M et al (2018) Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J Clin Invest 128, 4654-4668 https://doi.org/10.1172/JCI99317
  54. Lanuza PM, Vigueras A, Olivan S et al (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 https://doi.org/10.1080/2162402X.2017.1395123
  55. Hwang S, Han J, Baek JS et al (2019) Cytotoxicity of human hepatic intrasinusoidal CD56(bright) natural killer cells against hepatocellular carcinoma cells. Int J Mol Sci 20, 1564 https://doi.org/10.3390/ijms20071564
  56. Judge SJ, Dunai C, Aguilar EG et al (2020) Minimal PD-1 expression in mouse and human NK cells under diverse conditions. J Clin Invest 130, 3051-3068 https://doi.org/10.1172/jci133353
  57. Quatrini L, Wieduwild E, Escaliere B et al (2018) Endogenous glucocorticoids control host resistance to viral infection through the tissue-specific regulation of PD-1 expression on NK cells. Nat Immunol 19, 954-962 https://doi.org/10.1038/s41590-018-0185-0
  58. Anderson AC, Joller N and Kuchroo VK (2016) Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44, 989-1004 https://doi.org/10.1016/j.immuni.2016.05.001
  59. Rangachari M, Zhu C, Sakuishi K et al (2012) Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion. Nat Med 18, 1394-1400 https://doi.org/10.1038/nm.2871
  60. Carotta S (2016) Targeting NK cells for anticancer immunotherapy: clinical and preclinical approaches. Front Immunol 7, 152 https://doi.org/10.3389/fimmu.2016.00152
  61. Wang Z, Zhu J, Gu H et al (2015) The clinical significance of abnormal Tim-3 expression on NK cells from patients with gastric cancer. Immunol Invest 44, 578-589 https://doi.org/10.3109/08820139.2015.1052145
  62. Xu L, Huang Y, Tan L et al (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 https://doi.org/10.1016/j.intimp.2015.09.017
  63. Komita H, Koido S, Hayashi K et al (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 https://doi.org/10.3892/or.2015.4149
  64. Gallois A, Silva I, Osman I and Bhardwaj N (2014) Reversal of natural killer cell exhaustion by TIM-3 blockade. Oncoimmunology 3, e946365 https://doi.org/10.4161/21624011.2014.946365
  65. Zhang C and Liu Y (2020) Targeting NK cell checkpoint receptors or molecules for cancer immunotherapy. Front Immunol 11, 1295 https://doi.org/10.3389/fimmu.2020.01295
  66. Chauhan SKS, Koehl U and Kloess S (2020) Harnessing NK cell checkpoint-modulating immunotherapies. Cancers (Basel) 12, 1807 https://doi.org/10.3390/cancers12071807
  67. Van Audenaerde JRM, De Waele J, Marcq E et al (2017) Interleukin-15 stimulates natural killer cell-mediated killing of both human pancreatic cancer and stellate cells. Oncotarget 8, 56968-56979 https://doi.org/10.18632/oncotarget.18185
  68. Folgiero V, Cifaldi L, Li Pira G, Goffredo BM, Vinti L and Locatelli F (2015) TIM-3/Gal-9 interaction induces IFN gamma-dependent IDO1 expression in acute myeloid leukemia blast cells. J Hematol Oncol 8, 36 https://doi.org/10.1186/s13045-015-0134-4
  69. Markel G, Gruda R, Achdout H et al (2004) The critical role of residues 43R and 44Q of carcinoembryonic antigen cell adhesion molecules-1 in the protection from killing by human NK cells. J Immunol 173, 3732-3739 https://doi.org/10.4049/jimmunol.173.6.3732
  70. Fantini M, David JM, Annunziata CM, Morelli MP, Arlen PM and Tsang KY (2020) The monoclonal antibody NEO-201 enhances natural killer cell cytotoxicity against tumor cells through blockade of the inhibitory CEACAM5/CEACAM1 immune checkpoint pathway. Cancer Biother Radiopharm 35, 190-198 https://doi.org/10.1089/cbr.2019.3141
  71. Zeligs KP, Morelli MP, David JM et al (2020) Evaluation of the anti-tumor activity of the humanized monoclonal antibody NEO-201 in preclinical models of ovarian cancer. Front Oncol 10, 805 https://doi.org/10.3389/fonc.2020.00805
  72. Jacques A, Bleau C, Turbide C, Beauchemin N and Lamontagne L (2009) A synergistic interferon-gamma production is induced by mouse hepatitis virus in interleukin-12 (IL-12)/IL-18-activated natural killer cells and modulated by carcinoembryonic antigen-related cell adhesion molecules (CEACAM) 1a receptor. Immunology 128, e551-561
  73. Hosomi S, Chen Z, Baker K et al (2013) CEACAM1 on activated NK cells inhibits NKG2D-mediated cytolytic function and signaling. Eur J Immunol 43, 2473-2483 https://doi.org/10.1002/eji.201242676
  74. Kim WM, Huang YH, Gandhi A and Blumberg RS (2019) CEACAM1 structure and function in immunity and its therapeutic implications. Semin Immunol 42, 101296 https://doi.org/10.1016/j.smim.2019.101296
  75. Zhang Q, Bi J, Zheng X et al (2018) Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol 19, 723-732 https://doi.org/10.1038/s41590-018-0132-0
  76. Johnston RJ, Comps-Agrar L, Hackney J et al (2014) The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 26, 923-937 https://doi.org/10.1016/j.ccell.2014.10.018
  77. Gorvel L and Olive D (2020) Targeting the "PVR-TIGIT axis" with immune checkpoint therapies. F1000Res 9, 354 https://doi.org/10.12688/f1000research.22877.1
  78. Wang J, Sanmamed MF, Datar I et al (2019) Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell 176, 334-347 e312 https://doi.org/10.1016/j.cell.2018.11.010
  79. Maeda TK, Sugiura D, Okazaki IM, Maruhashi T and Okazaki T (2019) Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation. J Biol Chem 294, 6017-6026 https://doi.org/10.1074/jbc.ra119.007455
  80. Merino A, Zhang B, Dougherty P et al (2019) Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming. J Clin Invest 129, 3770-3785 https://doi.org/10.1172/JCI125916
  81. Brignone C, Grygar C, Marcu M, Schakel K and Triebel F (2007) A soluble form of lymphocyte activation gene-3 (IMP321) induces activation of a large range of human effector cytotoxic cells. J Immunol 179, 4202-4211 https://doi.org/10.4049/jimmunol.179.6.4202
  82. Brignone C, Escudier B, Grygar C, Marcu M and Triebel F (2009) A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma. Clin Cancer Res 15, 6225-6231 https://doi.org/10.1158/1078-0432.CCR-09-0068
  83. Brignone C, Gutierrez M, Mefti F et al (2010) First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity. J Transl Med 8, 71 https://doi.org/10.1186/1479-5876-8-71
  84. Nath PR, Gangaplara A, Pal-Nath D et al (2018) CD47 expression in natural killer cells regulates homeostasis and modulates immune response to Lymphocytic choriomeningitis virus. Front Immunol 9, 2985 https://doi.org/10.3389/fimmu.2018.02985
  85. Nath PR, Pal-Nath D, Mandal A, Cam MC, Schwartz AL and Roberts DD (2019) Natural killer cell recruitment and activation are regulated by CD47 expression in the tumor microenvironment. Cancer Immunol Res 7, 1547-1561 https://doi.org/10.1158/2326-6066.cir-18-0367
  86. Valipour B, Abedelahi A, Naderali E et al (2020) Cord blood stem cell derived CD16(+) NK cells eradicated acute lymphoblastic leukemia cells using with anti-CD47 antibody. Life Sci 242, 117223 https://doi.org/10.1016/j.lfs.2019.117223
  87. Tsao LC, Crosby EJ, Trotter TN et al (2019) CD47 blockade augmentation of trastuzumab antitumor efficacy dependent on antibody-dependent cellular phagocytosis. JCI Insight 4, e131882 https://doi.org/10.1172/jci.insight.131882
  88. Allard B, Longhi MS, Robson SC and Stagg J (2017) The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev 276, 121-144 https://doi.org/10.1111/imr.12528
  89. Neo SY, Yang Y, Record J et al (2020) CD73 immune checkpoint defines regulatory NK cells within the tumor microenvironment. J Clin Invest 130, 1185-1198 https://doi.org/10.1172/jci128895
  90. Wang J and Matosevic S (2019) NT5E/CD73 as correlative factor of patient survival and natural killer cell infiltration in glioblastoma. J Clin Med 8, 1526 https://doi.org/10.3390/jcm8101526
  91. Chambers AM and Matosevic S (2019) Immunometabolic dysfunction of natural killer cells mediated by the Hypoxia-CD73 axis in solid tumors. Front Mol Biosci 6, 60 https://doi.org/10.3389/fmolb.2019.00060
  92. Zheng Y, Ma X, Su D et al (2020) The roles of Siglec7 and Siglec9 on natural killer cells in virus infection and tumour progression. J Immunol Res 2020, 6243819
  93. Hudak JE, Canham SM and Bertozzi CR (2014) Glycocalyx engineering reveals a Siglec-based mechanism for NK cell immunoevasion. Nat Chem Biol 10, 69-75 https://doi.org/10.1038/nchembio.1388
  94. Jandus C, Boligan KF, Chijioke O et al (2014) Interactions between Siglec-7/9 receptors and ligands influence NK cell-dependent tumor immunosurveillance. J Clin Invest 124, 1810-1820 https://doi.org/10.1172/JCI65899
  95. Hernandez-Caselles T, Miguel RC, Ruiz-Alcaraz AJ and Garcia-Penarrubia P (2019) CD33 (Siglec-3) Inhibitory function: role in the NKG2D/DAP10 activating pathway. J Immunol Res 2019, 6032141 https://doi.org/10.1155/2019/6032141
  96. Kohl U, Arsenieva S, Holzinger A and Abken H (2018) CAR T cells in trials: recent achievements and challenges that remain in the production of modified T cells for clinical applications. Hum Gene Ther 29, 559-568 https://doi.org/10.1089/hum.2017.254
  97. Maude SL, Laetsch TW, Buechner J et al (2018) Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 378, 439-448 https://doi.org/10.1056/NEJMoa1709866
  98. Ren J, Liu X, Fang C, Jiang S, June CH and Zhao Y (2017) Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin Cancer Res 23, 2255-2266 https://doi.org/10.1158/1078-0432.CCR-16-1300
  99. Georgiadis C, Preece R, Nickolay L et al (2018) Long terminal repeat CRISPR-CAR-coupled "universal" T cells mediate potent anti-leukemic effects. Mol Ther 26, 1215- 1227 https://doi.org/10.1016/j.ymthe.2018.02.025
  100. Liu X, Zhang Y, Cheng C et al (2017) CRISPR-Cas9-mediated multiplex gene editing in CAR-T cells. Cell Res 27, 154-157 https://doi.org/10.1038/cr.2016.142
  101. Shifrin N, Raulet DH and Ardolino M (2014) NK cell self tolerance, responsiveness and missing self recognition. Semin Immunol 26, 138-144 https://doi.org/10.1016/j.smim.2014.02.007
  102. Cheng M, Chen YY, Xiao WH, Sun R and Tian ZG (2013) NK cell-based immunotherapy for malignant diseases. Cell Mol Immunol 10, 230-252 https://doi.org/10.1038/cmi.2013.10
  103. Liu E, Tong Y, Dotti G et al (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 https://doi.org/10.1038/leu.2017.226
  104. Li Y, Hermanson DL, Moriarity BS and Kaufman DS (2018) Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell 23, 181-192 e185 https://doi.org/10.1016/j.stem.2018.06.002
  105. Rezvani K, Rouce R, Liu E and Shpall E (2017) Engineering natural killer cells for cancer immunotherapy. Mol Ther 25, 1769-1781 https://doi.org/10.1016/j.ymthe.2017.06.012
  106. Suck G, Odendahl M, Nowakowska P et al (2016) NK-92: an 'off-the-shelf therapeutic' for adoptive natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother 65, 485-492 https://doi.org/10.1007/s00262-015-1761-x
  107. Karschnia P, Jordan JT, Forst DA et al (2019) Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells. Blood 133, 2212-2221 https://doi.org/10.1182/blood-2018-12-893396
  108. Veluchamy JP, Kok N, van der Vliet HJ, Verheul HMW, de Gruijl TD and 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 https://doi.org/10.3389/fimmu.2017.00631
  109. Moretta A (2002) Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol 2, 957-964 https://doi.org/10.1038/nri956
  110. Wang WX, Jiang JT and Wu CP (2020) CAR-NK for tumor immunotherapy: clinical transformation and future prospects. Cancer Letters 472, 175-180 https://doi.org/10.1016/j.canlet.2019.11.033
  111. Liu E, Marin D, Banerjee P et al (2020) Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med 382, 545-553 https://doi.org/10.1056/NEJMoa1910607
  112. Ruella M, Barrett DM, Kenderian SS et al (2016) Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J Clin Invest 126, 3814-3826 https://doi.org/10.1172/JCI87366
  113. Orlando EJ, Han X, Tribouley C et al (2018) Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat Med 24, 1504-1506 https://doi.org/10.1038/s41591-018-0146-z
  114. Sayitoglu EC, Georgoudaki AM, Chrobok M et al (2020) Boosting natural killer cell-mediated targeting of sarcoma through DNAM-1 and NKG2D. Front Immunol 11, 40 https://doi.org/10.3389/fimmu.2020.00040
  115. Barrow AD, Martin CJ and Colonna M (2019) The natural cytotoxicity receptors in health and disease. Front Immunol 10, 909 https://doi.org/10.3389/fimmu.2019.00909
  116. Zhang C, Oberoi P, Oelsner S et al (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 https://doi.org/10.3389/fimmu.2017.00533
  117. Dotti G, Gottschalk S, Savoldo B and Brenner MK (2014) Design and development of therapies using chimeric antigen receptor-expressing T cells. Immunol Rev 257, 107-126 https://doi.org/10.1111/imr.12131
  118. Sadelain M, Brentjens R and Riviere I (2013) The basic principles of chimeric antigen receptor design. Cancer Discov 3, 388-398 https://doi.org/10.1158/2159-8290.CD-12-0548
  119. Chmielewski M, Hombach A, Heuser C, Adams GP and Abken H (2004) T cell activation by antibody-like immunoreceptors: Increase in affinity of the single-chain fragment domain above threshold does not increase T cell activation against antigen-positive target cells but decreases selectivity. J Immunol 173, 7647-7653 https://doi.org/10.4049/jimmunol.173.12.7647
  120. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM and Rosenberg SA (2010) Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 18, 843-851 https://doi.org/10.1038/mt.2010.24
  121. Burger MC, Zhang CC, Harter PN et al (2019) CAR-engineered NK cells for the treatment of glioblastoma: turning innate effectors into precision tools for cancer immunotherapy. Front Immunol 10, 2683 https://doi.org/10.3389/fimmu.2019.02683
  122. Anderson P, Caligiuri M, Ritz J and Schlossman SF (1989) Cd3-negative natural-killer cells express Zeta-Tcr as part of a novel molecular-complex. Nature 341, 159-162 https://doi.org/10.1038/341159a0
  123. Kofler DM, Chmielewski M, Rappl G et al (2011) CD28 costimulation impairs the efficacy of a redirected T-cell antitumor attack in the presence of regulatory T cells which can be overcome by preventing Lck activation. Mol Ther 19, 760-767 https://doi.org/10.1038/mt.2011.9
  124. Topfer K, Cartellieri M, Michen S et al (2015) DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. J Immunol 194, 3201-3212 https://doi.org/10.4049/jimmunol.1400330
  125. Chang ZL and Chen YY (2017) CARs: synthetic immunoreceptors for cancer therapy and beyond. Trends Mol Med 23, 430-450 https://doi.org/10.1016/j.molmed.2017.03.002
  126. Alabanza L, Pegues M, Geldres C et al (2017) Function of novel anti-CD19 chimeric antigen receptors with human variable regions is affected by hinge and transmembrane domains. Mol Ther 25, 2452-2465 https://doi.org/10.1016/j.ymthe.2017.07.013
  127. Brentjens RJ, Riviere I, Park JH et al (2011) Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118, 4817-4828 https://doi.org/10.1182/blood.v118.21.4817.4817
  128. Long AH, Haso WM, Shern JF et al (2015) 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med 21, 581-590 https://doi.org/10.1038/nm.3838
  129. Salter AI, Ivey RG, Kennedy JJ et al (2018) Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function. Sci Signal 11, eaat6753 https://doi.org/10.1126/scisignal.aat6753
  130. Kershaw MH, Westwood JA, Parker LL et al (2006) A phase I study on adoptive immunotherapy using genemodified T cells for ovarian cancer. Clin Cancer Res 12, 6106-6115 https://doi.org/10.1158/1078-0432.ccr-06-1183
  131. Sahm C, Schonfeld K and Wels WS (2012) Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumorspecific antigen receptor. Cancer Immunol Immunother 61, 1451-1461 https://doi.org/10.1007/s00262-012-1212-x
  132. Cichocki F, Valamehr B, Bjordahl R et al (2017) GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. Cancer Res 77, 5664-5675 https://doi.org/10.1158/0008-5472.CAN-17-0799
  133. Kagoya Y, Tanaka S, Guo TX et al (2018) A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects. Nat Med 24, 352-359 https://doi.org/10.1038/nm.4478
  134. Chmielewski M and Abken H (2017) CAR T cells releasing IL-18 convert to T-Bet(high) FoxO1(low) effectors that exhibit augmented activity against advanced solid tumors. Cell Reports 21, 3205-3219 https://doi.org/10.1016/j.celrep.2017.11.063
  135. Chmielewski M and Abken H (2015) TRUCKs: the fourth generation of CARs. Expert Opin Biol Ther 15, 1145-1154 https://doi.org/10.1517/14712598.2015.1046430
  136. Hurton LV, Singh H, Najjar AM et al (2016) Tethered IL-15 augments antitumor activity and promotes a stemcell memory subset in tumor-specific T cells. Proc Natl Acad Sci U S A 113, E7788-E7797 https://doi.org/10.1073/pnas.1610544113
  137. Wang XM, Jasinski DL, Medina JL, Spencer DM, Foster AE and Bayle JH (2020) Inducible MyD88/CD40 synergizes with IL-15 to enhance antitumor efficacy of CAR-NK cells. Blood Adv 4, 1950-1964 https://doi.org/10.1182/bloodadvances.2020001510
  138. Mitwasi N, Feldmann A, Arndt C et al (2020) "UniCAR"-modified off-the-shelf NK-92 cells for targeting of GD2-expressing tumour cells. Sci Rep 10, 2141 https://doi.org/10.1038/s41598-020-59082-4
  139. Fabian KP, Padget MR, Donahue RN et al (2020) PD-L1 targeting high-affinity NK (t-haNK) cells induce direct antitumor effects and target suppressive MDSC populations. J Immunother Cancer 8, e000450 https://doi.org/10.1136/jitc-2019-000450
  140. Chang YH, Connolly J, Shimasaki N, Mimura K, Kono K and Campana D (2013) A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. Cancer Res 73, 1777-1786 https://doi.org/10.1158/0008-5472.CAN-12-3558
  141. Imamura M, Shook D, Kamiya T et al (2014) Autonomous growth and increased cytotoxicity of natural killer cells expressing membrane-bound interleukin-15. Blood 124, 1081-1088 https://doi.org/10.1182/blood-2014-02-556837