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Targeting natural killer cells in solid tumors

Cellular & Molecular Immunology volume 16, pages 415–422 (2019)Cite this article

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Abstract

Natural killer (NK) cells are innate lymphoid cells endowed with cytolytic activity and a capacity to secrete cytokines and chemokines. Several lines of evidence suggest that NK cells play an important role in anti-tumor immunity. Some therapies against hematological malignacies make use of the immune properties of NK cells, such as their ability to kill residual leukemic blasts efficiently after conditioning during haploidentical hematopoietic stem cell transplantation. However, knowledge on NK cell infiltration and the status of NK cell responsiveness in solid tumors is limited so far. The pro-angiogenic role of the recently described NK cell-like type 1 innate lymphoid cells (ILC1s) and their phenotypic resemblance to NK cells are confounding factors that add a level of complexity, at least in mice. Here, we review the current knowledge on the presence and function of NK cells in solid tumors as well as the immunotherapeutic approaches designed to harness NK cell functions in these conditions, including those that aim to reinforce conventional anti-tumor therapies to increase the chances of successful treatment.

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References

  1. Vivier, E. et al. Innate lymphoid cells: 10 years on. Cell 174, 1054–1066 (2018).

    Article  CAS  PubMed  Google Scholar 

  2. Shi, F. D., Ljunggren, H. G., La Cava, A. & Van Kaer, L. Organ-specific features of natural killer cells. Nat. Rev. Immunol. 11, 658–671 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Walzer, T. et al. Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46. Proc. Natl. Acad. Sci. USA 104, 3384–3389 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Biassoni, R., Bottino, C., Cantoni, C. & Moretta, A. Human natural killer receptors and their ligands. Curr. Protoc. Immunol. Chapter 14, Unit 14.10 (2002).

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

    Article  CAS  PubMed  Google Scholar 

  6. Guia, S., Fenis, A., Vivier, E. & Narni-Mancinelli, E. Activating and inhibitory receptors expressed on innate lymphoid cells. Semin. Immunopathol. 40, 331–341 (2018).

    Article  PubMed  Google Scholar 

  7. 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 

  8. Wu, N. & Veillette, A. SLAM family receptors in normal immunity and immune pathologies. Curr. Opin. Immunol. 38, 45–51 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Bryceson, Y. T., Ljunggren, H. G. & Long, E. O. Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors. Blood 114, 2657–2666 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bryceson, Y. T., March, M. E., Ljunggren, H. G. & Long, E. O. Activation, coactivation, and costimulation of resting human natural killer cells. Immunol. Rev. 214, 73–91 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Smyth, M. J. et al. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J. Exp. Med. 192, 755–760 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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 

  14. Vivier, E. et al. Innate or adaptive immunity? The example of natural killer cells. Science 331, 44–49 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Moretta, A. et al. Early liaisons between cells of the innate immune system in inflamed peripheral tissues. Trends Immunol. 26, 668–675 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Martin-Fontecha, A. et al. Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat. Immunol. 5, 1260–1265 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Hayakawa, Y. et al. IFN-gamma-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, alpha-galactosylceramide. Blood 100, 1728–1733 (2002).

    CAS  PubMed  Google Scholar 

  18. Krebs, P. et al. NK-cell-mediated killing of target cells triggers robust antigen-specific T-cell-mediated and humoral responses. Blood 113, 6593–6602 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Roder, J. C. et al. A new immunodeficiency disorder in humans involving NK cells. Nature 284, 553–555 (1980).

    Article  CAS  PubMed  Google Scholar 

  20. Sullivan, J. L., Byron, K. S., Brewster, F. E. & Purtilo, D. T. Deficient natural killer cell activity in x-linked lymphoproliferative syndrome. Science 210, 543–545 (1980).

    Article  CAS  PubMed  Google Scholar 

  21. Gorelik, E., Wiltrout, R. H., Okumura, K., Habu, S. & Herberman, R. B. Role of NK cells in the control of metastatic spread and growth of tumor cells in mice. Int J. Cancer 30, 107–112 (1982).

    Article  CAS  PubMed  Google Scholar 

  22. Talmadge, J. E., Meyers, K. M., Prieur, D. J. & Starkey, J. R. Role of natural killer cells in tumor growth and metastasis: C57BL/6 normal and beige mice. J. Natl. Cancer Inst. 65, 929–935 (1980).

    CAS  PubMed  Google Scholar 

  23. Nakajima, T., Mizushima, N., Nakamura, J. & Kanai, K. Surface markers of NK cells in peripheral blood of patients with cirrhosis and hepatocellular carcinoma. Immunol. Lett. 13, 7–10 (1986).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. Schantz, S. P., Shillitoe, E. J., Brown, B. & Campbell, B. Natural killer cell activity and head and neck cancer: a clinical assessment. J. Natl. Cancer Inst. 77, 869–875 (1986).

    CAS  PubMed  Google Scholar 

  26. Orange, J. S. Natural killer cell deficiency. J. Allergy Clin. Immunol. 132, 515–525 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Spinner, M. A. et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 123, 809–821 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gineau, L. et al. Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency. J. Clin. Invest. 122, 821–832 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Smyth, M. J., Hayakawa, Y., Takeda, K. & Yagita, H. New aspects of natural-killer-cell surveillance and therapy of cancer. Nat. Rev. Cancer 2, 850–861 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Lee, U., Santa, K., Habu, S. & Nishimura, T. Murine asialo GM1+CD8+T cells as novel interleukin-12-responsive killer T cell precursors. Jpn J. Cancer Res. 87, 429–432 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Trambley, J. et al. Asialo GM1(+) CD8(+) T cells play a critical role in costimulation blockade-resistant allograft rejection. J. Clin. Invest. 104, 1715–1722 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kataoka, S., Konishi, Y., Nishio, Y., Fujikawa-Adachi, K. & Tominaga, A. Antitumor activity of eosinophils activated by IL-5 and eotaxin against hepatocellular carcinoma. DNA Cell Biol. 23, 549–560 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Nishikado, H., Mukai, K., Kawano, Y., Minegishi, Y. & Karasuyama, H. NK cell-depleting anti-asialo GM1 antibody exhibits a lethal off-target effect on basophils in vivo. J. Immunol. 186, 5766–5771 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Slifka, M. K., Pagarigan, R. R. & Whitton, J. L. NK markers are expressed on a high percentage of virus-specific CD8+and CD4+T cells. J. Immunol. 164, 2009–2015 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Wiltrout, R. H. et al. Reactivity of anti-asialo GM1 serum with tumoricidal and non-tumoricidal mouse macrophages. J. Leukoc. Biol. 37, 597–614 (1985).

    Article  CAS  PubMed  Google Scholar 

  38. 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  PubMed Central  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  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Ruggeri, L. et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295, 2097–2100 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  44. 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  PubMed Central  CAS  Google Scholar 

  45. 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 

  46. 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 

  47. Erdag, G. et al. Immunotype and immunohistologic characteristics of tumor-infiltrating immune cells are associated with clinical outcome in metastatic melanoma. Cancer Res. 72, 1070–1080 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ali, T. H. et al. Enrichment of CD56(dim)KIR+CD57+highly cytotoxic NK cells in tumour-infiltrated lymph nodes of melanoma patients. Nat. Commun. 5, 5639 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Messaoudene, M. et al. Mature cytotoxic CD56(bright)/CD16(+) natural killer cells can infiltrate lymph nodes adjacent to metastatic melanoma. Cancer Res. 74, 81–92 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Denkert, C. et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 19, 40–50 (2018).

    Article  PubMed  Google Scholar 

  51. Salgado, R. et al. Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO Trial. JAMA Oncol. 1, 448–454 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Arnould, L. et al. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br. J. Cancer 94, 259–267 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gennari, R. et al. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin. Cancer Res. 10, 5650–5655 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Muller, P. et al. Trastuzumab emtansine (T-DM1) renders HER2+breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci. Transl. Med. 7, 315ra188 (2015).

    Article  PubMed  CAS  Google Scholar 

  55. Muntasell, A. et al. NK cell infiltrates and HLA class I expression in primary HER2+breast cancer predict and uncouple pathological response and disease-free survival. Clin. Cancer Res. 25, 1535–1545 (2019).

    Article  PubMed  CAS  Google Scholar 

  56. 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 

  57. 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 

  58. 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 

  59. 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 

  60. 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 

  61. Andre, P. et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 175, 1731–1743.e13 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Baumeister, S. H., Freeman, G. J., Dranoff, G. & Sharpe, A. H. Coinhibitory pathways in immunotherapy for cancer. Annu Rev. Immunol. 34, 539–573 (2016).

    Article  CAS  PubMed  Google Scholar 

  63. Okazaki, T., Chikuma, S., Iwai, Y., Fagarasan, S. & Honjo, T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat. Immunol. 14, 1212–1218 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Okazaki, T. & Honjo, T. PD-1 and PD-1 ligands: from discovery to clinical application. Int. Immunol. 19, 813–824 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).

    Article  CAS  PubMed  Google Scholar 

  66. Sharma, P. & Allison, J. P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Barry, K. C. et al. A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat. Med. 24, 1178–1191 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hsu, J. et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J. Clin. Invest. 128, 4654–4668 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Dougall, W. C., Kurtulus, S., Smyth, M. J. & Anderson, A. C. TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy. Immunol. Rev. 276, 112–120 (2017).

    Article  CAS  PubMed  Google Scholar 

  71. Anderson, A. C., Joller, N. & Kuchroo, V. K. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44, 989–1004 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lavin, Y. et al. Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell 169, 750–765.e17 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 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 

  74. 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 

  75. Castriconi, R. et al. Neuroblastoma-derived TGF-beta1 modulates the chemokine receptor repertoire of human resting NK cells. J. Immunol. 190, 5321–5328 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Gubbels, J. A. et al. MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells. Mol. Cancer 9, 11 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Balsamo, M. et al. Melanoma cells become resistant to NK-cell-mediated killing when exposed to NK-cell numbers compatible with NK-cell infiltration in the tumor. Eur. J. Immunol. 42, 1833–1842 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Pogge von Strandmann, E. et al. Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. Immunity 27, 965–974 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. 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  PubMed Central  Google Scholar 

  80. Horton, N. C., Mathew, S. O. & Mathew, P. A. Novel interaction between proliferating cell nuclear antigen and HLA I on the surface of tumor cells inhibits NK cell function through NKp44. PLoS ONE 8, e59552 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Rosental, B. et al. Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44. J. Immunol. 187, 5693–5702 (2011).

    Article  CAS  PubMed  Google Scholar 

  82. Hoechst, B. et al. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 50, 799–807 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Li, T. et al. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett. 318, 154–161 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Li, T. et al. Colorectal carcinoma-derived fibroblasts modulate natural killer cell phenotype and antitumor cytotoxicity. Med. Oncol. 30, 663 (2013).

    Article  PubMed  CAS  Google Scholar 

  85. Castriconi, R. et al. Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc. Natl. Acad. Sci. USA 100, 4120–4125 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Marcenaro, E. et al. IL-12 or IL-4 prime human NK cells to mediate functionally divergent interactions with dendritic cells or tumors. J. Immunol. 174, 3992–3998 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Pietra, G. et al. Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity. Cancer Res. 72, 1407–1415 (2012).

    Article  CAS  PubMed  Google Scholar 

  88. 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 

  89. Lee, J. et al. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. Cancer Immunol. Res. 7, 219–229 (2019).

    Article  PubMed  CAS  Google Scholar 

  90. 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 

  91. Alvarez, I. B. et al. Role played by the programmed death-1-programmed death ligand pathway during innate immunity against Mycobacterium tuberculosis. J. Infect. Dis. 202, 524–532 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Norris, S. et al. PD-1 expression on natural killer cells and CD8(+) T cells during chronic HIV-1 infection. Viral Immunol. 25, 329–332 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Benson, D. M. 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  PubMed Central  Google Scholar 

  94. Amaria, R. N. et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat. Med. 24, 1649–1654 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Liu, D. et al. Chimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV. Protein Cell 8, 861–877 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 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 

  97. Lonez, C. et al. Study protocol for THINK: a multinational open-label phase I study to assess the safety and clinical activity of multiple administrations of NKR-2 in patients with different metastatic tumour types. BMJ Open 7, e017075 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Gasteiger, G., Fan, X., Dikiy, S., Lee, S. Y. & Rudensky, A. Y. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science 350, 981–985 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Peng, H. et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J. Clin. Invest. 123, 1444–1456 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Klose, C. S. N. et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell 157, 340–356 (2014).

    Article  CAS  PubMed  Google Scholar 

  101. Abt, M. C. et al. Innate immune defenses mediated by two ILC subsets are critical for protection against acute Clostridium difficile infection. Cell Host Microbe 18, 27–37 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Weizman, O. E. et al. ILC1 confer early host protection at initial sites of viral infection. Cell 171, 795–808 e712 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Freud, A. G. et al. NKp80 defines a critical step during human natural killer cell development. Cell Rep. 16, 379–391 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 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).

    Article  CAS  PubMed  Google Scholar 

  105. Nussbaum, K. et al. Tissue microenvironment dictates the fate and tumor-suppressive function of type 3 ILCs. J. Exp. Med. 214, 2331–2347 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Vonarbourg, C. et al. Regulated expression of nuclear receptor RORgammat confers distinct functional fates to NK cell receptor-expressing RORgammat(+) innate lymphocytes. Immunity 33, 736–751 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hazenberg, M. D. & Spits, H. Human innate lymphoid cells. Blood 124, 700–709 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Judge, C. J. et al. CD56(bright) NK IL-7Ralpha expression negatively associates with HCV level, and IL-7-induced NK function is impaired during HCV and HIV infections. J. Leukoc. Biol. 102, 171–184 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Fuchs, A. ILC1s in tissue inflammation and infection. Front. Immunol. 7, 104 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Michel, T. et al. Human CD56bright NK cells: an update. J. Immunol. 196, 2923–2931 (2016).

    Article  CAS  PubMed  Google Scholar 

  112. Poli, A. et al. CD56bright natural killer (NK) cells: an important NK cell subset. Immunology 126, 458–465 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lima, M. et al. Chemokine receptor expression on normal blood CD56(+) NK-cells elucidates cell partners that comigrate during the innate and adaptive immune responses and identifies a transitional NK-cell population. J. Immunol. Res. 2015, 839684 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Mittal, D., Vijayan, D. & Smyth, M. J. Overcoming acquired PD-1/PD-L1 resistance with CD38 blockade. Cancer Discov. 8, 1066–1068 (2018).

    Article  CAS  PubMed  Google Scholar 

  115. Lopez-Verges, S. et al. CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+NK-cell subset. Blood 116, 3865–3874 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kloverpris, H. N. et al. Innate lymphoid cells are depleted irreversibly during acute HIV-1 infection in the absence of viral suppression. Immunity 44, 391–405 (2016).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  117. Cruz-Zarate, D. et al. Innate lymphoid cells have decreased HLA-DR expression but retain their responsiveness to TLR ligands during sepsis. J. Immunol. 201, 3401–3410 (2018).

    Article  CAS  PubMed  Google Scholar 

  118. Moretta, L. Dissecting CD56dim human NK cells. Blood 116, 3689–3691 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

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 program (Targeting innate lymphoid cells (TILC), grant agreement number 694502), the Agence Nationale de la Recherche (PIONeeR Project (ANR-17-RHUS-0007)), 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.

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Authors and Affiliations

  1. Innate Pharma, Marseille, France

    Guillaume Habif, Pascale André & Eric Vivier

  2. Aix Marseille Université, INSERM, CNRS, Centre d’Immunologie de Marseille-Luminy, Marseille, France

    Adeline Crinier, Eric Vivier & Emilie Narni-Mancinelli

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

    Eric Vivier

Authors
  1. Guillaume Habif
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  2. Adeline Crinier
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  3. Pascale André
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  4. Eric Vivier
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  5. Emilie Narni-Mancinelli
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Corresponding author

Correspondence to Emilie Narni-Mancinelli.

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Competing interests

G.H., P.A. and E.V. are employees of Innate Pharma. The other authors declare no competing interests.

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Habif, G., Crinier, A., André, P. et al. Targeting natural killer cells in solid tumors. Cell Mol Immunol 16, 415–422 (2019). https://doi.org/10.1038/s41423-019-0224-2

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