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  • Review Article
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Natural killer cells and other innate lymphoid cells in cancer

Nature Reviews Immunology volume 18, pages 671–688 (2018)Cite this article

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A Correction to this article was published on 12 October 2018

Abstract

Immuno-oncology is an emerging field that has revolutionized cancer treatment. Most immunomodulatory strategies focus on enhancing T cell responses, but there has been a recent surge of interest in harnessing the relatively underexplored natural killer (NK) cell compartment for therapeutic interventions. NK cells show cytotoxic activity against diverse tumour cell types, and some of the clinical approaches originally developed to increase T cell cytotoxicity may also activate NK cells. Moreover, increasing numbers of studies have identified novel methods for increasing NK cell antitumour immunity and expanding NK cell populations ex vivo, thereby paving the way for a new generation of anticancer immunotherapies. The role of other innate lymphoid cells (group 1 innate lymphoid cell (ILC1), ILC2 and ILC3 subsets) in tumours is also being actively explored. This Review provides an overview of the field and summarizes current immunotherapeutic approaches for solid tumours and haematological malignancies.

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Fig. 1: Cell surface receptors expressed by human and mouse ILCs.
Fig. 2: Crosstalk between natural killer cells and tumour cells.
Fig. 3: Pleiotropic roles of ILC1s, ILC2s and ILC3s in cancer.
Fig. 4: Therapeutic approaches to restore NK cell-mediated tumour cell lysis.

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References

  1. Bottcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Pallmer, K. & Oxenius, A. Recognition and regulation of T cells by NK cells. Front. Immunol. 7, 251 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Ferlazzo, G. & Moretta, L. Dendritic cell editing by natural killer cells. Crit. Rev. Oncog. 19, 67–75 (2014).

    Article  PubMed  Google Scholar 

  4. Morandi, B. et al. Dendritic cell editing by activated natural killer cells results in a more protective cancer-specific immune response. PLOS One 7, e39170 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Zhang, Q. et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat. Immunol. 19, 723–732 (2018).

    Article  CAS  PubMed  Google Scholar 

  6. Mirchandani, A. S. et al. Type 2 innate lymphoid cells drive CD4+ Th2 cell responses. J. Immunol. 192, 2442–2448 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Saranchova, I. et al. Type 2 innate lymphocytes actuate immunity against tumours and limit cancer metastasis. Sci. Rep. 8, 2924 (2018).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Robinette, M. L. & Colonna, M. Innate lymphoid cells and the MHC. HLA 87, 5–11 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Smyth, M. J. et al. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J. Exp. Med. 192, 755–760 (2000). This publication demonstrates that perforin-mediated tumour cell lysis controls in vivo tumour growth.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Street, S. E. et al. Host perforin reduces tumor number but does not increase survival in oncogene-driven mammary adenocarcinoma. Cancer Res. 67, 5454–5460 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Trinchieri, G. Biology of natural killer cells. Adv. Immunol. 47, 187–376 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Smyth, M. J., Crowe, N. Y. & Godfrey, D. I. NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int. Immunol. 13, 459–463 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Smyth, M. J. et al. Differential tumor surveillance by natural killer (NK) and NKT cells. J. Exp. Med. 191, 661–668 (2000).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Glasner, A. et al. Recognition and prevention of tumor metastasis by the NK receptor NKp46/NCR1. J. Immunol. 188, 2509–2515 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Halfteck, G. G. et al. Enhanced in vivo growth of lymphoma tumors in the absence of the NK-activating receptor NKp46/NCR1. J. Immunol. 182, 2221–2230 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Glasner, A. et al. NKp46 receptor-mediated interferon-γ production by natural killer cells increases fibronectin 1 to alter tumor architecture and control metastasis. Immunity 48, 107–119 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. Finnberg, N., Klein-Szanto, A. J. & El-Deiry, W. S. TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis. J. Clin. Invest. 118, 111–123 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Ebbo, M. et al. Low circulating natural killer cell counts are associated with severe disease in patients with common variable immunodeficiency. EBioMedicine 6, 222–230 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  19. Brittenden, J., Heys, S. D., Ross, J. & Eremin, O. Natural killer cells and cancer. Cancer 77, 1226–1243 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Schantz, S. P., Campbell, B. H. & Guillamondegui, O. M. Pharyngeal carcinoma and natural killer cell activity. Am. J. Surg. 152, 467–474 (1986).

    Article  CAS  PubMed  Google Scholar 

  21. Schantz, S. P. & Ordonez, N. G. Quantitation of natural killer cell function and risk of metastatic poorly differentiated head and neck cancer. Nat. Immun. Cell Growth Regul. 10, 278–288 (1991).

    CAS  PubMed  Google Scholar 

  22. Schantz, S. P., Savage, H. E., Racz, T., Taylor, D. L. & Sacks, P. G. Natural killer cells and metastases from pharyngeal carcinoma. Am. J. Surg. 158, 361–366 (1989).

    Article  CAS  PubMed  Google Scholar 

  23. Pross, H. F. & Lotzova, E. Role of natural killer cells in cancer. Nat. Immun. 12, 279–292 (1993).

    CAS  PubMed  Google Scholar 

  24. Imai, K., Matsuyama, S., Miyake, S., Suga, K. & Nakachi, K. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet 356, 1795–1799 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Tartter, P. I., Steinberg, B., Barron, D. M. & Martinelli, G. The prognostic significance of natural killer cytotoxicity in patients with colorectal cancer. Arch. Surg. 122, 1264–1268 (1987).

    Article  CAS  PubMed  Google Scholar 

  26. Garcia-Iglesias, T. et al. Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions. BMC Cancer 9, 186 (2009).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Eckl, J. et al. Transcript signature predicts tissue NK cell content and defines renal cell carcinoma subgroups independent of TNM staging. J. Mol. Med. 90, 55–66 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Platonova, S. et al. Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. Cancer Res. 71, 5412–5422 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Carrega, P. et al. Natural killer cells infiltrating human nonsmall-cell lung cancer are enriched in CD56 bright CD16(-) cells and display an impaired capability to kill tumor cells. Cancer 112, 863–875 (2008).

    Article  PubMed  Google Scholar 

  30. Schleypen, J. S. et al. Renal cell carcinoma-infiltrating natural killer cells express differential repertoires of activating and inhibitory receptors and are inhibited by specific HLA class I allotypes. Int. J. Cancer 106, 905–912 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Schleypen, J. S. et al. Cytotoxic markers and frequency predict functional capacity of natural killer cells infiltrating renal cell carcinoma. Clin. Cancer Res. 12, 718–725 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Faveeuw, C., Di Mauro, M. E., Price, A. A. & Ager, A. Roles of alpha(4) integrins/VCAM-1 and LFA-1/ICAM-1 in the binding and transendothelial migration of T lymphocytes and T lymphoblasts across high endothelial venules. Int. Immunol. 12, 241–251 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Halama, N. et al. Natural killer cells are scarce in colorectal carcinoma tissue despite high levels of chemokines and cytokines. Clin. Cancer Res. 17, 678–689 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Molgora, M. et al. IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity. Nature 551, 110–114 (2017).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Delconte, R. B. et al. CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nat. Immunol. 17, 816–824 (2016).

    Article  CAS  PubMed  Google Scholar 

  36. Paolino, M. et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507, 508–512 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ruggeri, L. et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood 94, 333–339 (1999).

    CAS  PubMed  Google Scholar 

  38. Ruggeri, L. et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295, 2097–2100 (2002). References 37 and 38 describe the occurrence of NK cell alloreactivity against AML blasts after HLA-mismatched transplantation, which occurred without exacerbating graft-versus-host disease.

    Article  CAS  PubMed  Google Scholar 

  39. Hsu, K. C. et al. Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes. Blood 105, 4878–4884 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Cooley, S. et al. Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood 116, 2411–2419 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Stringaris, K. et al. Leukemia-induced phenotypic and functional defects in natural killer cells predict failure to achieve remission in acute myeloid leukemia. Haematologica 99, 836–847 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Sarkar, S. et al. Optimal selection of natural killer cells to kill myeloma: the role of HLA-E and NKG2A. Cancer Immunol. Immunother. 64, 951–963 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Hejazi, M. et al. Impaired cytotoxicity associated with defective natural killer cell differentiation in myelodysplastic syndromes. Haematologica 100, 643–652 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Coles, S. J. et al. CD200 expression suppresses natural killer cell function and directly inhibits patient anti-tumor response in acute myeloid leukemia. Leukemia 25, 792–799 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Benson, D. M. Jr 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 116, 2286–2294 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Vari, F. et al. 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 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Cifaldi, L. et al. Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome. Arthritis Rheumatol. 67, 3037–3046 (2015).

    Article  CAS  PubMed  Google Scholar 

  48. Ponzetta, A. et al. Multiple myeloma impairs bone marrow localization of effector natural killer cells by altering the chemokine microenvironment. Cancer Res. 75, 4766–4777 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Costello, R. T. et al. Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia. Blood 99, 3661–3667 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Hughes, A. et al. CML patients with deep molecular responses to TKI have restored immune effectors and decreased PD-1 and immune suppressors. Blood 129, 1166–1176 (2017).

    Article  CAS  PubMed  Google Scholar 

  51. Fauriat, C. et al. 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 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Chretien, A. S. et al. NKp46 expression on NK cells as a prognostic and predictive biomarker for response to allo-SCT in patients with AML. Oncoimmunology 6, e1307491 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  53. Chretien, A. S. et al. NKp30 expression is a prognostic immune biomarker for stratification of patients with intermediate-risk acute myeloid leukemia. Oncotarget 8, 49548–49563 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  54. Sanchez-Correa, B. et al. Decreased expression of DNAM-1 on NK cells from acute myeloid leukemia patients. Immunol. Cell Biol. 90, 109–115 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Carlsten, M. et al. Reduced DNAM-1 expression on bone marrow NK cells associated with impaired killing of CD34+ blasts in myelodysplastic syndrome. Leukemia 24, 1607–1616 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Torelli, G. F. et al. Recognition of adult and pediatric acute lymphoblastic leukemia blasts by natural killer cells. Haematologica 99, 1248–1254 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Szczepanski, M. J., Szajnik, M., Welsh, A., Whiteside, T. L. & Boyiadzis, M. Blast-derived microvesicles in sera from patients with acute myeloid leukemia suppress natural killer cell function via membrane-associated transforming growth factor-beta1. Haematologica 96, 1302–1309 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Hilpert, J. et al. Comprehensive analysis of NKG2D ligand expression and release in leukemia: implications for NKG2D-mediated NK cell responses. J. Immunol. 189, 1360–1371 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Epling-Burnette, P. K. et al. Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors. Blood 109, 4816–4824 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Jinushi, M. et al. MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proc. Natl Acad. Sci. USA 105, 1285–1290 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zocchi, M. R. et al. High ERp5/ADAM10 expression in lymph node microenvironment and impaired NKG2D ligands recognition in Hodgkin lymphomas. Blood 119, 1479–1489 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Ferrari de Andrade, L. et al. Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity. Science 359, 1537–1542 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Reiners, K. S. et al. Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity. Blood 121, 3658–3665 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Baessler, T. et al. CD137 ligand mediates opposite effects in human and mouse NK cells and impairs NK-cell reactivity against human acute myeloid leukemia cells. Blood 115, 3058–3069 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Nuebling, T. et al. The immune checkpoint modulator OX40 and its ligand OX40L in NK-cell immunosurveillance and acute myeloid leukemia. Cancer Immunol. Res. 6, 209–221 (2018).

    Article  CAS  PubMed  Google Scholar 

  66. Riether, C. et al. CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia. J. Exp. Med. 214, 359–380 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Simoni, Y. et al. Human innate lymphoid cell subsets possess tissue-type based heterogeneity in phenotype and frequency. Immunity 46, 148–161 (2017).

    Article  CAS  PubMed  Google Scholar 

  68. Carrega, P. et al. NCR(+)ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures. Nat. Commun. 6, 8280 (2015).

    Article  CAS  PubMed  Google Scholar 

  69. Dieu-Nosjean, M. C. et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J. Clin. Oncol. 26, 4410–4417 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Kirchberger, S. et al. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J. Exp. Med. 210, 917–931 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Irshad, S. et al. RORγt(+) innate lymphoid cells promote lymph node metastasis of breast cancers. Cancer Res. 77, 1083–1096 (2017).

    Article  CAS  PubMed  Google Scholar 

  72. Munneke, J. M. et al. Activated innate lymphoid cells are associated with a reduced susceptibility to graft-versus-host disease. Blood 124, 812–821 (2014). This article suggests that activated ILCs following HSCT can protect against graft-versus-host disease.

    Article  CAS  PubMed  Google Scholar 

  73. Trabanelli, S. et al. CD127+ innate lymphoid cells are dysregulated in treatment naive acute myeloid leukemia patients at diagnosis. Haematologica 100, e257–e260 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. de Weerdt, I. et al. Innate lymphoid cells are expanded and functionally altered in chronic lymphocytic leukemia. Haematologica 101, e461–e464 (2016).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Kini Bailur, J. et al. Changes in bone marrow innate lymphoid cell subsets in monoclonal gammopathy: target for IMiD therapy. Blood Adv. 1, 2343–2347 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  76. Romano, M. et al. Mutations in JAK2 and Calreticulin genes are associated with specific alterations of the immune system in myelofibrosis. Oncoimmunology 6, e1345402 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  77. Trabanelli, S. et al. Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis. Nat. Commun. 8, 593 (2017). This article deciphers a new tolerogenic pathway involving interactions between PGD 2 and B7-H6 on tumour cells and CRTH2 and NKp30 on ILC2s, which in turn activate MDSCs via IL-13 secretion, inducing an immunosuppressive microenvironment that facilitates tumour immunoescape.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Dadi, S. et al. Cancer immunosurveillance by tissue-resident innate lymphoid cells and innate-like T cells. Cell 164, 365–377 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Mlecnik, B. et al. Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients. Sci. Transl Med. 6, 228ra37 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Gao, Y. et al. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nat. Immunol. 18, 1004–1015 (2017).

    CAS  PubMed  Google Scholar 

  81. Cortez, V. S. et al. SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-beta signaling. Nat. Immunol. 18, 995–1003 (2017). Publications 80 and 81 describe a novel mechanism of TGFβ-driven tumour immune escape.

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Stanietsky, N. et al. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc. Natl Acad. Sci. USA 106, 17858–17863 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Otegbeye, F. et al. Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in AML and colon cancer models. PLOS One 13, e0191358 (2018).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Fuchs, A. et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells. Immunity 38, 769–781 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Karvellas, C. J., Fedorak, R. N., Hanson, J. & Wong, C. K. Increased risk of colorectal cancer in ulcerative colitis patients diagnosed after 40 years of age. Can. J. Gastroenterol. 21, 443–446 (2007).

    Article  PubMed Central  PubMed  Google Scholar 

  86. Levin, A. D., Wildenberg, M. E. & van den Brink, G. R. Mechanism of action of anti-TNF therapy in inflammatory bowel disease. J. Crohns Colitis 10, 989–997 (2016).

    Article  PubMed  Google Scholar 

  87. Popivanova, B. K. et al. Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J. Clin. Invest. 118, 560–570 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Bernink, J. H. et al. Interleukin-12 and -23 control plasticity of CD127(+) group 1 and group 3 innate lymphoid cells in the intestinal lamina propria. Immunity 43, 146–160 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Goldszmid, R. S. et al. NK cell-derived interferon-gamma orchestrates cellular dynamics and the differentiation of monocytes into dendritic cells at the site of infection. Immunity 36, 1047–1059 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Bie, Q. et al. Polarization of ILC2s in peripheral blood might contribute to immunosuppressive microenvironment in patients with gastric cancer. J. Immunol. Res. 2014, 923135 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Di Stefano, A. B. et al. Survivin is regulated by interleukin-4 in colon cancer stem cells. J. Cell. Physiol. 225, 555–561 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Zhou, R., Qian, S., Gu, X., Chen, Z. & Xiang, J. Interleukin-13 and its receptors in colorectal cancer (Review). Biomed. Rep. 1, 687–690 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Jovanovic, I. P. et al. Interleukin-33/ST2 axis promotes breast cancer growth and metastases by facilitating intratumoral accumulation of immunosuppressive and innate lymphoid cells. Int. J. Cancer 134, 1669–1682 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Tomas, A., Futter, C. E. & Eden, E. R. EGF receptor trafficking: consequences for signaling and cancer. Trends Cell Biol. 24, 26–34 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  95. Hams, E. et al. IL-25 and type 2 innate lymphoid cells induce pulmonary fibrosis. Proc. Natl Acad. Sci. USA 111, 367–372 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. McHedlidze, T. et al. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 39, 357–371 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  97. Lim, A. I. et al. IL-12 drives functional plasticity of human group 2 innate lymphoid cells. J. Exp. Med. 213, 569–583 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  98. Ikutani, M. et al. Identification of innate IL-5-producing cells and their role in lung eosinophil regulation and antitumor immunity. J. Immunol. 188, 703–713 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Eisenring, M., vom Berg, J., Kristiansen, G., Saller, E. & Becher, B. IL-12 initiates tumor rejection via lymphoid tissue-inducer cells bearing the natural cytotoxicity receptor NKp46. Nat. Immunol. 11, 1030–1038 (2010). This article provides evidence that a non-NK ILC population can control tumour growth.

    Article  CAS  PubMed  Google Scholar 

  100. Ebbo, M., Crinier, A., Vely, F. & Vivier, E. Innate lymphoid cells: major players in inflammatory diseases. Nat. Rev. Immunol. 17, 665–678 (2017).

    Article  CAS  PubMed  Google Scholar 

  101. Chan, I. H. et al. Interleukin-23 is sufficient to induce rapid de novo gut tumorigenesis, independent of carcinogens, through activation of innate lymphoid cells. Mucosal Immunol. 7, 842–856 (2014).

    Article  CAS  PubMed  Google Scholar 

  102. Jiang, R. et al. IL-22 is related to development of human colon cancer by activation of STAT3. BMC Cancer 13, 59 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  103. Roy, S. & Trinchieri, G. Microbiota: a key orchestrator of cancer therapy. Nat. Rev. Cancer 17, 271–285 (2017).

    Article  CAS  PubMed  Google Scholar 

  104. Wu, T. et al. Elevated serum IL-22 levels correlate with chemoresistant condition of colorectal cancer. Clin. Immunol. 147, 38–39 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Hernandez, P., Gronke, K. & Diefenbach, A. A catch-22: Interleukin-22 and cancer. Eur. J. Immunol. 48, 15–31 (2018).

    Article  CAS  PubMed  Google Scholar 

  106. Crome, S. Q. et al. A distinct innate lymphoid cell population regulates tumor-associated T cells. Nat. Med. 23, 368–375 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  107. Romagne, F. et al. Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells. Blood 114, 2667–2677 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  108. Kohrt, H. E. et al. 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 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  109. Benson, D. M. Jr et al. IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect. Blood 118, 6387–6391 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  110. Fernandez, N. C. et al. A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules. Blood 105, 4416–4423 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  111. Kim, S. et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436, 709–713 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Anfossi, N. et al. Human NK cell education by inhibitory receptors for MHC class I. Immunity 25, 331–342 (2006). This article indicates that NK cells lacking inhibitory KIRs for self MHC class I are hyporesponsive against MHC class I-deficient cells, suggesting that KIR–MHC class I interactions are crucial for NK cell education in humans.

    Article  CAS  PubMed  Google Scholar 

  113. Carlsten, M. et al. 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 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Mamessier, E. et al. Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J. Clin. Invest. 121, 3609–3622 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  115. Collins, S. M. et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol. Immunother. 62, 1841–1849 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  116. Bezman, N. A. et al. PD-1 blockade enhances elotuzumab efficacy in mouse tumor models. Blood Adv. 1, 753–765 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  117. Hagner, P. R. et al. Activity of lenalidomide in mantle cell lymphoma can be explained by NK cell-mediated cytotoxicity. Br. J. Haematol. 179, 399–409 (2017).

    Article  CAS  PubMed  Google Scholar 

  118. Zitvogel, L., Rusakiewicz, S., Routy, B., Ayyoub, M. & Kroemer, G. Immunological off-target effects of imatinib. Nat. Rev. Clin. Oncol. 13, 431–446 (2016).

    Article  CAS  PubMed  Google Scholar 

  119. Kreutzman, A. et al. Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy. Blood 116, 772–782 (2010).

    Article  CAS  PubMed  Google Scholar 

  120. Vergoulidou, M. More than a decade of tyrosine kinase inhibitors in the treatment of solid tumors: what we have learned and what the future holds. Biomark. Insights 10 (Suppl. 3), 33–40 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Beatty, G. L. et al. First-in-human phase I study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin. Cancer Res. 23, 3269–3276 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  122. Levin, A. M. et al. Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’. Nature 484, 529–533 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  123. Charych, D. H. et al. NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. Clin. Cancer Res. 22, 680–690 (2016).

    Article  CAS  PubMed  Google Scholar 

  124. Sockolosky, J. T. et al. Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes. Science 359, 1037–1042 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  125. Mao, C. et al. Interleukin-2 as maintenance therapy for children and adults with acute myeloid leukaemia in first complete remission. Cochrane Database Syst. Rev. 11, CD010248 (2015).

    Google Scholar 

  126. Szczepanski, M. J. et al. Interleukin-15 enhances natural killer cell cytotoxicity in patients with acute myeloid leukemia by upregulating the activating NK cell receptors. Cancer Immunol. Immunother. 59, 73–79 (2010).

    Article  CAS  PubMed  Google Scholar 

  127. Wagner, J. A. et al. CD56bright NK cells exhibit potent antitumor responses following IL-15 priming. J. Clin. Invest. 127, 4042–4058 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  128. Felices, M. et al. Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect. JCI Insight 3, e96219 (2018).

    Article  PubMed Central  Google Scholar 

  129. Gleason, M. K. et al. CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets. Blood 123, 3016–3026 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  130. Vallera, D. A. et al. IL15 trispecific killer engagers (TriKE) make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Clin. Cancer Res. 22, 3440–3450 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  131. Geller, M. A. et al. A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy 13, 98–107 (2011).

    Article  CAS  PubMed  Google Scholar 

  132. Granzin, M. et al. Shaping of natural killer cell antitumor activity by ex vivo cultivation. Front. Immunol. 8, 458 (2017).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  133. Chu, J. et al. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Leukemia 28, 917–927 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. Jiang, H. et al. Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells. Mol. Oncol. 8, 297–310 (2014).

    Article  CAS  PubMed  Google Scholar 

  135. Kloss, S. et al. 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 (2017).

    Article  CAS  PubMed  Google Scholar 

  136. Chang, Y. H. et al. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. Cancer Res. 73, 1777–1786 (2013).

    Article  CAS  PubMed  Google Scholar 

  137. O’Sullivan, T. et al. Interleukin-17D mediates tumor rejection through recruitment of natural killer cells. Cell Rep. 7, 989–998 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  138. Tang, H. et al. Facilitating T cell infiltration in tumor microenvironment overcomes resistance to PD-L1 blockade. Cancer Cell 29, 285–296 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  139. Putz, E. M. et al. NK cell heparanase controls tumor invasion and immune surveillance. J. Clin. Invest. 127, 2777–2788 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  140. Makkouk, A. et al. Characterizing CD137 upregulation on NK cells in patients receiving monoclonal antibody therapy. Ann. Oncol. 28, 415–420 (2017).

    CAS  PubMed  Google Scholar 

  141. Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293 (2015).

    Article  CAS  PubMed  Google Scholar 

  142. Moretta, L. et al. Surface NK receptors and their ligands on tumor cells. Semin. Immunol. 18, 151–158 (2006).

    Article  CAS  PubMed  Google Scholar 

  143. Moretta, A. et al. Receptors for HLA class-I molecules in human natural killer cells. Annu. Rev. Immunol. 14, 619–648 (1996).

    Article  CAS  PubMed  Google Scholar 

  144. Ortaldo, J.R. & Young, H.A. Mouse Ly49 NK receptors: balancing activation and inhibition. Molecular Immunology 42, 445–450 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. Tomasello, E. et al. Mapping of NKp46+ cells in healthy human lymphoid and non-lymphoid tissues. Front. Immunol. 3, 344 (2012).

    Article  PubMed Central  PubMed  Google Scholar 

  146. Narni-Mancinelli, E. et al. Fate mapping analysis of lymphoid cells expressing the NKp46 cell surface receptor. Proc. Natl Acad. Sci. 108, 18324–18329 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Glatzer, T. et al. RORγt+ innate lymphoid cells acquire a proinflammatory program upon engagement of the activating receptor NKp44. Immunity 38, 1223–1235 (2013).

    Article  CAS  PubMed  Google Scholar 

  148. Killig, M., Glatzer, T. & Romagnani, C. Recognition strategies of group 3 innate lymphoid cells. Front. Immunol. 5, 142 (2014).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  149. Salimi, M. et al. Group 2 innate lymphoid cells express functional NKp30 receptor inducing type 2 cytokine production. J. Immunol. 196, 45–54 (2016).

    Article  CAS  PubMed  Google Scholar 

  150. Vely, F. et al. Evidence of innate lymphoid cell redundancy in humans. Nat. Immunol. 17, 1291–1299 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  151. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  152. Lee, J. C., Lee, K. M., Kim, D. W. & Heo, D. S. Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J. Immunol. 172, 7335–7340 (2004).

    Article  CAS  PubMed  Google Scholar 

  153. Cortez, V. S. et al. Transforming growth factor-β signaling guides the differentiation of innate lymphoid cells in salivary glands. Immunity 44, 1127–1139 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  154. Vitale, M., Cantoni, C., Pietra, G., Mingari, M. C. & Moretta, L. Effect of tumor cells and tumor microenvironment on NK-cell function. Eur. J. Immunol. 44, 1582–1592 (2014).

    Article  CAS  PubMed  Google Scholar 

  155. Zingoni, A. et al. Targeting NKG2D and NKp30 ligands shedding to improve NK cell-based immunotherapy. Crit. Rev. Immunol. 36, 445–460 (2016).

    Article  PubMed  Google Scholar 

  156. Wang, W. et al. Tumor-released Galectin-3, a soluble inhibitory ligand of human NKp30, plays an important role in tumor escape from NK cell attack. J. Biol. Chem. 289, 33311–33319 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  157. Xiao, Q. et al. DKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation. Nat. Med. 24, 262–270 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  159. Krzywinska, E. et al. Loss of HIF-1alpha in natural killer cells inhibits tumour growth by stimulating non-productive angiogenesis. Nat. Commun. 8, 1597 (2017).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  160. Spranger, S. & Gajewski, T. F. Impact of oncogenic pathways on evasion of antitumour immune responses. Nat. Rev. Cancer 18, 139–147 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Lopez-Soto, A. et al. Epithelial-mesenchymal transition induces an antitumor immune response mediated by NKG2D receptor. J. Immunol. 190, 4408–4419 (2013).

    Article  CAS  PubMed  Google Scholar 

  162. Sathe, P. et al. Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells. Nat. Commun. 5, 4539 (2014).

    Article  CAS  PubMed  Google Scholar 

  163. Ishigami, S. et al. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 88, 577–583 (2000).

    Article  CAS  PubMed  Google Scholar 

  164. Coca, S. et al. The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer 79, 2320–2328 (1997).

    Article  CAS  PubMed  Google Scholar 

  165. Donskov, F. & von der Maase, H. Impact of immune parameters on long-term survival in metastatic renal cell carcinoma. J. Clin. Oncol. 24, 1997–2005 (2006).

    Article  PubMed  Google Scholar 

  166. Pasero, C. et al. Inherent and tumor-driven immune tolerance in the prostate microenvironment impairs natural killer cell antitumor activity. Cancer Res. 76, 2153–2165 (2016).

    Article  CAS  PubMed  Google Scholar 

  167. Rhim, A. D. et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349–361 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  168. Hosseini, H. et al. Early dissemination seeds metastasis in breast cancer. Nature 540, 552–558 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Harper, K. L. et al. Mechanism of early dissemination and metastasis in Her2(+) mammary cancer. Nature 540, 588–592 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Lopez-Soto, A., Gonzalez, S., Smyth, M. J. & Galluzzi, L. Control of metastasis by NK cells. Cancer Cell 32, 135–154 (2017).

    Article  CAS  PubMed  Google Scholar 

  171. Maurer, S. et al. Platelet-mediated shedding of NKG2D ligands impairs NK cell immune-surveillance of tumor cells. Oncoimmunology 7, e1364827 (2018).

    Article  PubMed  Google Scholar 

  172. Bastid, J. et al. Inhibition of CD39 enzymatic function at the surface of tumor cells alleviates their immunosuppressive activity. Cancer Immunol. Res. 3, 254–265 (2015).

    Article  CAS  PubMed  Google Scholar 

  173. Gao, Z. W., Dong, K. & Zhang, H. Z. The roles of CD73 in cancer. Biomed. Res. Int. 2014, 460654 (2014).

    PubMed Central  PubMed  Google Scholar 

  174. Lee, H. et al. A novel pro-angiogenic function for interferon-γ-secreting natural killer cells. Invest. Ophthalmol. Vis. Sci. 55, 2885–2892 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  175. Taylor, S. et al. PD-1 regulates KLRG1+ group 2 innate lymphoid cells. J. Exp. Med. 214, 1663–1678 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  176. Maazi, H. et al. ICOS:ICOS-ligand interaction is required for type 2 innate lymphoid cell function, homeostasis, and induction of airway hyperreactivity. Immunity 42, 538–551 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  177. Barrow, A. D. et al. Natural killer cells control tumor growth by sensing a growth factor. Cell 172, 534–548 (2018).

    Article  CAS  PubMed  Google Scholar 

  178. Pende, D. et al. Analysis of the receptor-ligand interactions in the natural killer-mediated lysis of freshly isolated myeloid or lymphoblastic leukemias: evidence for the involvement of the Poliovirus receptor (CD155) and Nectin-2 (CD112). Blood 105, 2066–2073 (2005).

    Article  CAS  PubMed  Google Scholar 

  179. Mastaglio, S. et al. Natural killer receptor ligand expression on acute myeloid leukemia impacts survival and relapse after chemotherapy. Blood Adv. 2, 335–346 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  180. Salih, H. R. et al. Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood 102, 1389–1396 (2003).

    Article  CAS  PubMed  Google Scholar 

  181. Chretien, A. S. et al. Natural killer defective maturation is associated with adverse clinical outcome in patients with acute myeloid leukemia. Front. Immunol. 8, 573 (2017).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  182. Chretien, A. S. et al. Increased NK cell maturation in patients with acute myeloid leukemia. Front. Immunol. 6, 564 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  183. Rea, D. et al. Natural killer-cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study. Haematologica 102, 1368–1377 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Hara, R. et al. NKG2D gene polymorphisms are associated with disease control of chronic myeloid leukemia by dasatinib. Int. J. Hematol. 106, 666–674 (2017).

    Article  PubMed  Google Scholar 

  185. Boissel, N. et al. BCR/ABL oncogene directly controls MHC class I chain-related molecule A expression in chronic myelogenous leukemia. J. Immunol. 176, 5108–5116 (2006).

    Article  CAS  PubMed  Google Scholar 

  186. El-Sherbiny, Y. M. et al. The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells. Cancer Res. 67, 8444–8449 (2007).

    Article  CAS  PubMed  Google Scholar 

  187. Costello, R. T. et al. Differential expression of natural killer cell activating receptors in blood versus bone marrow in patients with monoclonal gammopathy. Immunology 139, 338–341 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

The laboratory of E.V. is supported by funding from the European Research Council (ERC) under the European Union Horizon 2020 research and innovation programme (Targeting innate lymphoid cells (TILC), grant agreement number 694502); the Agence Nationale de la Recherche, Equipe Labellisée “La Ligue”, Ligue Nationale contre le Cancer, MSDAvenir, Innate Pharma and institutional grants to the CIML (Institut National Français de Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille University) and to Marseille Immunopôle. P.-Y.D. is a fellow of the Fondation de France. M.V. is a recipient of an individual PhD grant from the Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation. The authors thank M. Blery, Y. Morel and S. Cornen for helpful comments.

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Nature Reviews Immunology thanks M. Smyth and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Innate Pharma Research Labs, Innate Pharma, Marseille, France

    Laura Chiossone & Eric Vivier

  2. Aix Marseille University, CNRS, INSERM, CIML, Marseille, France

    Laura Chiossone, Pierre-Yves Dumas, Margaux Vienne & Eric Vivier

  3. CHU Bordeaux, Service d’Hématologie Clinique et Thérapie Cellulaire, F-33000, Bordeaux, France

    Pierre-Yves Dumas

  4. Service d’Immunologie, Marseille Immunopole, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France

    Eric Vivier

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E.V., L.C., P.-Y.D. and M.V. contributed to researching data, discussion of content and the writing of this article. E.V., L.C. and P.-Y.D. reviewed and edited the manuscript.

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Correspondence to Eric Vivier.

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Supplementary information

Glossary

Asialo-GM1

The cell surface glycolipid GM1 with its sialic acid groups removed. Asiolo-GM1 is expressed by natural killer cells and also by a subset of T cells and myeloid cells.

NK1.1

An activating C-type lectin receptor that is expressed by natural killer cells and natural killer T cells in C57Bl/6 mice.

Natural killer cell p46-related protein

(NKp46). An activating receptor that is expressed by human and mouse natural killer cells and subsets of group 1 innate lymphoid cells (ILC1s) and ILC3s.

Killer cell immunoglobulin-like receptors

(KIRs). A family of receptors (including CD158) for MHC class I molecules that are expressed on natural killer (NK) cells and a subset of T cells. They regulate NK cell activation and tolerance.

Leukocyte immunoglobulin-like receptor subfamily B member 1

(LIR1). A receptor for a broad range of MHC class I molecules that is expressed by monocytes, natural killer cells, T cells and B cells. Engagement of LIR1 results in inhibitory immune signalling.

The ‘missing ligand’ model

A model that postulates that a natural killer (NK) cell-mediated graft-versus-leukaemia effect will also occur when the donor NK cells express an inhibitory killer cell immunoglobulin-like receptor (KIR) for which neither donor nor recipient expresses a relevant MHC class I ligand.

The ‘donor haplotype’ model

A model suggesting that assessing donor killer cell immunoglobulin-like receptor (KIR) haplotypes is important for determining the efficacy of haematopoietic stem cell transplantation; KIR gene clusters include haplotype A, which contains predominantly inhibitory KIRs, and haplotype B, whose members are more diverse.

CD57

A suggested marker for replicative senescence. CD57 is absent on fetal natural killer (NK) cells, increases with age and defines a subpopulation of highly differentiated circulating NK cells.

Natural cytotoxicity receptors

(NCRs). A family of activating receptors (including natural killer cell p30-related protein (NKp30), NKp44 and NKp46) that is selectively expressed by innate lymphoid cells.

Pomalidomide

An anti-angiogenic and immunomodulatory drug that is a derivative of thalidomide.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of immature myeloid cells that rapidly expand during inflammation and are able to downregulate immune responses.

Amphiregulin

A member of the epidermal growth factor (EGF) family that signals through the EGF receptor (EGFR).

Bispecific killer cell engagers

(BiKEs). Bispecific monoclonal antibodies that bind activating natural killer cell receptors at one end and tumour antigens at the other.

Trispecific killer cell engagers

(TriKEs). Molecules containing two antibody fragments, which are directed against an activating natural killer cell receptor and a tumour antigen, and an immune stimulatory cytokine crosslinker.

Rituximab

A cytotoxic antibody directed against CD20 that destroys both normal and malignant B cells and is therefore used to treat diseases characterized by having too many B cells.

Lenalidomide

A derivative of thalidomide that inhibits tumour angiogenesis and tumour cell proliferation.

Durvalumab

An antibody that blocks programmed cell death 1 ligand 1 (PDL1).

Cetuximab

An antibody that blocks epidermal growth factor receptor (EGFR).

ALT803

An IL-15–IL-15 receptor subunit-α (IL-15Rα) complex fused to an IgG1 crystallizable fragment (Fc) domain; in this construct, IL-15 is additionally mutated to increase its biological activity.

Melphalan

A chemotherapy drug that acts as an alkylating agent.

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Chiossone, L., Dumas, PY., Vienne, M. et al. Natural killer cells and other innate lymphoid cells in cancer. Nat Rev Immunol 18, 671–688 (2018). https://doi.org/10.1038/s41577-018-0061-z

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