Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

NK cells for cancer immunotherapy

Abstract

Natural killer (NK) cells can swiftly kill multiple adjacent cells if these show surface markers associated with oncogenic transformation. This property, which is unique among immune cells, and their capacity to enhance antibody and T cell responses support a role for NK cells as anticancer agents. Although tumours may develop several mechanisms to resist attacks from endogenous NK cells, ex vivo activation, expansion and genetic modification of NK cells can greatly increase their antitumour activity and equip them to overcome resistance. Some of these methods have been translated into clinical-grade platforms and support clinical trials of NK cell infusions in patients with haematological malignancies or solid tumours, which have yielded encouraging results so far. The next generation of NK cell products will be engineered to enhance activating signals and proliferation, suppress inhibitory signals and promote their homing to tumours. These modifications promise to significantly increase their clinical activity. Finally, there is emerging evidence of increased NK cell-mediated tumour cell killing in the context of molecularly targeted therapies. These observations, in addition to the capacity of NK cells to magnify immune responses, suggest that NK cells are poised to become key components of multipronged therapeutic strategies for cancer.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Activating and inhibitory NK receptors and their corresponding ligands.
Fig. 2: Sources and methods for isolation, activation and propagation of allogeneic NK cells.
Fig. 3: Genetic modification approaches to increase the antitumour capacity of NK cells.
Fig. 4: Scenarios for interaction between NK cells and other immune cells in the tumour microenvironment.

Similar content being viewed by others

References

  1. June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Herberman, R. B., Nunn, M. E. & Lavrin, D. H. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity. Int. J. Cancer 16, 216–229 (1975).

    CAS  PubMed  Google Scholar 

  4. Morvan, M. G. & Lanier, L. L. NK cells and cancer: you can teach innate cells new tricks. Nat. Rev. Cancer 16, 7–19 (2015).

    Google Scholar 

  5. Guillerey, C., Huntington, N. D. & Smyth, M. J. Targeting natural killer cells in cancer immunotherapy. Nat. Immunol. 17, 1025–1036 (2016).

    CAS  PubMed  Google Scholar 

  6. 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).

    CAS  PubMed  Google Scholar 

  7. Ruggeri, L. et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295, 2097–2100 (2002). This landmark study demonstrates the antileukaemic effect of allogeneic NK cells in mice and correlates the KIR profile with outcome in patients with AML after HSCT.

    CAS  PubMed  Google Scholar 

  8. Miller, J. S. et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in cancer patients. Blood 105, 3051–3057 (2005). This pioneering study demonstrates that infusion of allogeneic activated NK cells can induce major responses in patients with AML and highlights the importance of lymphodepleting therapy in creating a cytokine milieu supportive of NK cell expansion after infusion.

    CAS  PubMed  Google Scholar 

  9. Rubnitz, J. E. et al. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J. Clin. Oncol. 28, 955–959 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Cooley, S. et al. First-in-human trial of rhIL-15 and haploidentical natural killer cell therapy for advanced acute myeloid leukemia. Blood Adv. 3, 1970–1980 (2019). This article describes the first trial of recombinant human IL-15 administered after NK cell infusions in patients with AML, reporting NK cell expansion and toxic effects.

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  12. Lanier, L. L., Testi, R., Bindl, J. & Phillips, J. H. Identity of Leu-19 (CD56) leukocyte differentiation antigen and neural cell adhesion molecule. J. Exp. Med. 169, 2233–2238 (1989).

    CAS  PubMed  Google Scholar 

  13. Sivori, S. et al. p46, a novel natural killer cell-specific surface molecule that mediates cell activation. J. Exp. Med. 186, 1129–1136 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Freud, A. G. et al. Expression of the activating receptor, NKp46 (CD335), in human natural killer and T-cell neoplasia. Am. J. Clin. Pathol. 140, 853–866 (2013).

    CAS  PubMed  Google Scholar 

  15. Yu, J., Freud, A. G. & Caligiuri, M. A. Location and cellular stages of natural killer cell development. Trends Immunol. 34, 573–582 (2013).

    CAS  PubMed  Google Scholar 

  16. Lanier, L. L., Spits, H. & Phillips, J. H. The developmental relationship between NK cells and T cells. Immunol. Today 13, 392–395 (1992).

    CAS  PubMed  Google Scholar 

  17. Renoux, V. M. et al. Identification of a human natural killer cell lineage-restricted progenitor in fetal and adult tissues. Immunity 43, 394–407 (2015).

    CAS  PubMed  Google Scholar 

  18. Schlums, H. et al. Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells. Blood 129, 1927–1939 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Corat, M. A. et al. Acquired somatic mutations in PNH reveal long-term maintenance of adaptive NK cells independent of HSPCs. Blood 129, 1940–1946 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang, Y. et al. In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection. Immunology 121, 258–265 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Lutz, C. T. et al. Human NK cells proliferate and die in vivo more rapidly than T cells in healthy young and elderly adults. J. Immunol. 186, 4590–4598 (2011).

    CAS  PubMed  Google Scholar 

  22. Fujisaki, H., Kakuda, H., Imai, C., Mullighan, C. G. & Campana, D. Replicative potential of human natural killer cells. Br. J. Haematol. 145, 606–613 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. O’Sullivan, T. E., Sun, J. C. & Lanier, L. L. Natural killer cell memory. Immunity 43, 634–645 (2015).

    PubMed  PubMed Central  Google Scholar 

  24. Adams, N. M. et al. Cytomegalovirus infection drives avidity selection of natural killer cells. Immunity 50, 1381–1390.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Reeves, R. K. et al. Antigen-specific NK cell memory in rhesus macaques. Nat. Immunol. 16, 927–932 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Hammer, Q., Ruckert, T. & Romagnani, C. Natural killer cell specificity for viral infections. Nat. Immunol. 19, 800–808 (2018).

    CAS  PubMed  Google Scholar 

  27. Nikzad, R. et al. Human natural killer cells mediate adaptive immunity to viral antigens. Sci. Immunol. 4, eaat8116 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Hammer, Q. et al. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Nat. Immunol. 19, 453–463 (2018).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  30. Raulet, D. H. & Vance, R. E. Self-tolerance of natural killer cells. Nat. Rev. Immunol. 6, 520–531 (2006).

    CAS  PubMed  Google Scholar 

  31. Elliott, J. M. & Yokoyama, W. M. Unifying concepts of MHC-dependent natural killer cell education. Trends Immunol. 32, 364–372 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Brodin, P., Lakshmikanth, T., Johansson, S., Karre, K. & Hoglund, P. The strength of inhibitory input during education quantitatively tunes the functional responsiveness of individual natural killer cells. Blood 113, 2434–2441 (2009).

    CAS  PubMed  Google Scholar 

  33. Guia, S. et al. Confinement of activating receptors at the plasma membrane controls natural killer cell tolerance. Sci. Signal. 4, ra21 (2011).

    PubMed  Google Scholar 

  34. Staaf, E. et al. Educated natural killer cells show dynamic movement of the activating receptor NKp46 and confinement of the inhibitory receptor Ly49A. Sci. Signal. 11, eaai9200 (2018).

    PubMed  PubMed Central  Google Scholar 

  35. Goodridge, J. P. et al. Remodeling of secretory lysosomes during education tunes functional potential in NK cells. Nat. Commun. 10, 514 (2019).

    PubMed  PubMed Central  Google Scholar 

  36. Viant, C. et al. SHP-1-mediated inhibitory signals promote responsiveness and anti-tumour functions of natural killer cells. Nat. Commun. 5, 5108 (2014).

    CAS  PubMed  Google Scholar 

  37. Joncker, N. T., Shifrin, N., Delebecque, F. & Raulet, D. H. Mature natural killer cells reset their responsiveness when exposed to an altered MHC environment. J. Exp. Med. 207, 2065–2072 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Zamora, A. E. et al. Licensing delineates helper and effector NK cell subsets during viral infection. JCI Insight 2, e87032 (2017).

    PubMed Central  Google Scholar 

  39. Imai, C., Iwamoto, S. & Campana, D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood 106, 376–383 (2005). This is one of the first studies to show that a second-generation anti-CD19 CAR can be expressed in NK cells after ex vivo expansion, overcome inhibitory signals and trigger specific killing of B cell ALL.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Bauer, S. et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285, 727–729 (1999).

    CAS  PubMed  Google Scholar 

  41. Gasser, S., Orsulic, S., Brown, E. J. & Raulet, D. H. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature. 436, 1186–1190 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Narni-Mancinelli, E. et al. Complement factor P is a ligand for the natural killer cell-activating receptor NKp46. Sci. Immunol. 2, eaam9628 (2017).

    PubMed  PubMed Central  Google Scholar 

  43. Barrow, A. D. et al. Natural killer cells control tumor growth by sensing a growth factor. Cell 172, 534–548.e19 (2018). This article reports that PDGF-DD, produced by tumour cells, is a ligand for the NKp44 activating receptor and stimulates NK cell cytokine and chemokine secretion.

    CAS  PubMed  Google Scholar 

  44. Ferris, R. L., Jaffee, E. M. & Ferrone, S. Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoescape. J. Clin. Oncol. 28, 4390–4399 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Bournazos, S., Wang, T. T., Dahan, R., Maamary, J. & Ravetch, J. V. Signaling by antibodies: recent progress. Annu. Rev. Immunol. 35, 285–311 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Koene, H. R. et al. Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-48L/R/H phenotype. Blood 90, 1109–1114 (1997).

    CAS  PubMed  Google Scholar 

  47. Bryceson, Y. T., March, M. E., Ljunggren, H. G. & Long, E. O. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood 107, 159–166 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Trinchieri, G. et al. Response of resting human peripheral blood natural killer cells to interleukin 2. J. Exp. Med. 160, 1147–1169 (1984).

    CAS  PubMed  Google Scholar 

  49. Fujisaki, H. et al. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res. 69, 4010–4017 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Mukherjee, S. et al. In silico modeling identifies CD45 as a regulator of IL-2 synergy in the NKG2D-mediated activation of immature human NK cells. Sci. Signal. 10, eaai9062 (2017).

    PubMed  PubMed Central  Google Scholar 

  51. Fehniger, T. A. & Caligiuri, M. A. Interleukin 15: biology and relevance to human disease. Blood 97, 14–32 (2001).

    CAS  PubMed  Google Scholar 

  52. Prlic, M., Blazar, B. R., Farrar, M. A. & Jameson, S. C. In vivo survival and homeostatic proliferation of natural killer cells. J. Exp. Med. 197, 967–976 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Conlon, K. C. et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J. Clin. Oncol. 33, 74–82 (2015).

    CAS  PubMed  Google Scholar 

  54. Miller, J. S. et al. A first-in-human phase I study of subcutaneous outpatient recombinant human IL15 (rhIL15) in adults with advanced solid tumors. Clin. Cancer Res. 24, 1525–1535 (2018).

    CAS  PubMed  Google Scholar 

  55. Sliz, A. et al. Gab3 is required for IL-2- and IL-15-induced NK cell expansion and limits trophoblast invasion during pregnancy. Sci. Immunol. 4, eaav3866 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  57. Kobayashi, H. et al. Role of trans-cellular IL-15 presentation in the activation of NK cell-mediated killing, which leads to enhanced tumor immunosurveillance. Blood 105, 721–727 (2005).

    CAS  PubMed  Google Scholar 

  58. Chertova, E. et al. Characterization and favorable in vivo properties of heterodimeric soluble IL-15.IL-15Ralpha cytokine compared to IL-15 monomer. J. Biol. Chem. 288, 18093–18103 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Imamura, M. et al. Autonomous growth and increased cytotoxicity of natural killer cells expressing membrane-bound interleukin-15. Blood 124, 1081–1088 (2014). This article describes how expression of mbIL-15 in human NK cells sustains their growth and increases antitumour activity.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  61. Parrish-Novak, J. et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408, 57–63 (2000).

    CAS  PubMed  Google Scholar 

  62. Takaki, R. et al. IL-21 enhances tumor rejection through a NKG2D-dependent mechanism. J. Immunol. 175, 2167–2173 (2005).

    CAS  PubMed  Google Scholar 

  63. Fehniger, T. A. et al. Differential cytokine and chemokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: implications for the innate immune response. J. Immunol. 162, 4511–4520 (1999).

    CAS  PubMed  Google Scholar 

  64. Kasaian, M. T. et al. IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity 16, 559–569 (2002).

    CAS  PubMed  Google Scholar 

  65. Cooper, M. A. et al. Cytokine-induced memory-like natural killer cells. Proc. Natl Acad. Sci. USA 106, 1915–1919 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Romee, R. et al. Cytokine activation induces human memory-like NK cells. Blood 120, 4751–4760 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Ni, J., Miller, M., Stojanovic, A., Garbi, N. & Cerwenka, A. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. J. Exp. Med. 209, 2351–2365 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Saez-Borderias, A. et al. IL-12-dependent inducible expression of the CD94/NKG2A inhibitory receptor regulates CD94/NKG2C+ NK cell function. J. Immunol. 182, 829–836 (2009).

    CAS  PubMed  Google Scholar 

  69. Marcus, A. et al. Tumor-derived cGAMP triggers a STING-mediated interferon response in non-tumor cells to activate the NK cell response. Immunity 49, 754–763 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Timonen, T., Ortaldo, J. R. & Herberman, R. B. Characteristics of human large granular lymphocytes and relationship to natural killer and K cells. J. Exp. Med. 153, 569–582 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Orange, J. S. Formation and function of the lytic NK-cell immunological synapse. Nat. Rev. Immunol. 8, 713–725 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Gwalani, L. A. & Orange, J. S. Single degranulations in NK cells can mediate target cell killing. J. Immunol. 200, 3231–3243 (2018).

    CAS  PubMed  Google Scholar 

  73. Liu, D. et al. Integrin-dependent organization and bidirectional vesicular traffic at cytotoxic immune synapses. Immunity 31, 99–109 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Betts, M. R. et al. Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J. Immunol. Methods 281, 65–78 (2003).

    CAS  PubMed  Google Scholar 

  75. Prager, I. et al. NK cells switch from granzyme B to death receptor-mediated cytotoxicity during serial killing. J. Exp. Med. 216, 2113–2127 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Bottcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037 (2018). This article reports how NK cells increase the number of dendritic cells in tumour sites by secreting the chemoattractans CCL5 and XCL1, and that NK cell/dendritic cell gene signatures correlate with outcome in several cancer types.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Barry, K. C. et al. A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat. Med. 24, 1178–1191 (2018). This article describes how NK cells, through secretion of FLT3L, control the abundance of intratumoural stimulatory dendritic cells and how their frequency directly correlates with survival in patients with melanoma receiving anti-PD-1 therapy.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Takeda, K. et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat. Med. 7, 94–100 (2001).

    CAS  PubMed  Google Scholar 

  80. Takeda, K. et al. Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J. Exp. Med. 195, 161–169 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Street, S. E. et al. Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gammadelta T cells. J. Exp. Med. 199, 879–884 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Guerra, N. et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 28, 571–580 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Lorenzi, L. et al. Occurrence of nodular lymphocyte-predominant Hodgkin lymphoma in Hermansky-Pudlak type 2 syndrome is associated to natural killer and natural killer T cell defects. PLOS ONE 8, e80131 (2013).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 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).

    CAS  PubMed  Google Scholar 

  87. Albertsson, P. A. et al. NK cells and the tumour microenvironment: implications for NK-cell function and anti-tumour activity. Trends Immunol. 24, 603–609 (2003).

    CAS  PubMed  Google Scholar 

  88. Mandal, R. et al. The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight 1, e89829 (2016).

    PubMed  PubMed Central  Google Scholar 

  89. Delahaye, N. F. et al. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat. Med. 17, 700–707 (2011).

    CAS  PubMed  Google Scholar 

  90. Semeraro, M., Rusakiewicz, S., Zitvogel, L. & Kroemer, G. Natural killer cell mediated immunosurveillance of pediatric neuroblastoma. Oncoimmunology 4, e1042202 (2015).

    PubMed  PubMed Central  Google Scholar 

  91. 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, 228ra237 (2014).

    Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  93. Gooden, M. et al. HLA-E expression by gynecological cancers restrains tumor-infiltrating CD8+ T lymphocytes. Proc. Natl Acad. Sci. USA 108, 10656–10661 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Malmberg, K. J. et al. Natural killer cell-mediated immunosurveillance of human cancer. Semin. Immunol. 31, 20–29 (2017).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  96. Raulet, D. H., Gasser, S., Gowen, B. G., Deng, W. & Jung, H. Regulation of ligands for the NKG2D activating receptor. Annu. Rev. Immunol. 31, 413–441 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Paczulla, A. M. et al. Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature 572, 254–259 (2019). This article provides evidence for a potential mechanism of resistance to NK cells in AML caused by lower expression of NKG2D ligands in leukaemia stem cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Chitadze, G. et al. Shedding of endogenous MHC class I-related chain molecules A and B from different human tumor entities: heterogeneous involvement of the “a disintegrin and metalloproteases” 10 and 17. Int. J. Cancer 133, 1557–1566 (2013).

    CAS  PubMed  Google Scholar 

  99. Chitadze, G., Bhat, J., Lettau, M., Janssen, O. & Kabelitz, D. Generation of soluble NKG2D ligands: proteolytic cleavage, exosome secretion and functional implications. Scand. J. Immunol. 78, 120–129 (2013).

    CAS  PubMed  Google Scholar 

  100. Groh, V., Wu, J., Yee, C. & Spies, T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419, 734–738 (2002).

    CAS  PubMed  Google Scholar 

  101. Salih, H. R., Rammensee, H. G. & Steinle, A. Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding. J. Immunol. 169, 4098–4102 (2002).

    CAS  PubMed  Google Scholar 

  102. Salih, H. R., Goehlsdorf, D. & Steinle, A. Release of MICB molecules by tumor cells: mechanism and soluble MICB in sera of cancer patients. Hum. Immunol. 67, 188–195 (2006).

    CAS  PubMed  Google Scholar 

  103. Fernandez-Messina, L. et al. Differential mechanisms of shedding of the glycosylphosphatidylinositol (GPI)-anchored NKG2D ligands. J. Biol. Chem. 285, 8543–8551 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Coudert, J. D. et al. Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells. Blood 106, 1711–1717 (2005).

    CAS  PubMed  Google Scholar 

  106. Crane, C. A. et al. Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients. Proc. Natl Acad. Sci. USA 111, 12823–12828 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Thompson, T. W. et al. Endothelial cells express NKG2D ligands and desensitize antitumor NK responses. eLife 6, e30881 (2017).

    PubMed  PubMed Central  Google Scholar 

  108. Deng, W. et al. Antitumor immunity. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection. Science 348, 136–139 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Braud, V. M. et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391, 795–799 (1998).

    CAS  PubMed  Google Scholar 

  110. Lazetic, S., Chang, C., Houchins, J. P., Lanier, L. L. & Phillips, J. H. Human natural killer cell receptors involved in MHC class I recognition are disulfide-linked heterodimers of CD94 and NKG2 subunits. J. Immunol. 157, 4741–4745 (1996).

    CAS  PubMed  Google Scholar 

  111. Houchins, J. P., Lanier, L. L., Niemi, E. C., Phillips, J. H. & Ryan, J. C. Natural killer cell cytolytic activity is inhibited by NKG2-A and activated by NKG2-C. J. Immunol. 158, 3603–3609 (1997).

    CAS  PubMed  Google Scholar 

  112. Malmberg, K. J. et al. IFN-gamma protects short-term ovarian carcinoma cell lines from CTL lysis via a CD94/NKG2A-dependent mechanism. J. Clin. Invest. 110, 1515–1523 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Kamiya, T., Seow, S. V., Wong, D., Robinson, M. & Campana, D. Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells. J. Clin. Invest. 129, 2094–2106 (2019).

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. de Kruijf, E. M. et al. HLA-E and HLA-G expression in classical HLA class I-negative tumors is of prognostic value for clinical outcome of early breast cancer patients. J. Immunol. 185, 7452–7459 (2010).

    PubMed  Google Scholar 

  116. Andersson, E. et al. Non-classical HLA-class I expression in serous ovarian carcinoma: correlation with the HLA-genotype, tumor infiltrating immune cells and prognosis. Oncoimmunology 5, e1052213 (2016).

    PubMed  Google Scholar 

  117. Concha-Benavente, F. et al. PD-L1 mediates dysfunction in activated PD-1+ NK cells in head and neck cancer patients. Cancer Immunol. Res. 6, 1548–1560 (2018).

    PubMed  PubMed Central  Google Scholar 

  118. Ohs, I. et al. Restoration of natural killer cell antimetastatic activity by IL12 and checkpoint blockade. Cancer Res. 77, 7059–7071 (2017).

    CAS  PubMed  Google Scholar 

  119. Hsu, J. et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J. Clin. Invest. 128, 4654–4668 (2018). This article describes how PD-1–PD-L1 interaction inhibits NK cell responses and how NK cells contribute to the enhanced antitumour immune reactivity brought about by PD-1/PD-L1 blockade.

    PubMed  PubMed Central  Google Scholar 

  120. Viel, S. et al. TGF-beta inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci. Signal. 9, ra19 (2016).

    PubMed  Google Scholar 

  121. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 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 

  123. Rautela, J. et al. Therapeutic blockade of activin-A improves NK cell function and antitumor immunity. Sci. Signal. 12, eaat7527 (2019).

    PubMed  Google Scholar 

  124. Frumento, G. et al. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J. Exp. Med. 196, 459–468 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Young, A. et al. A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment. Cancer Res. 78, 1003–1016 (2018).

    CAS  PubMed  Google Scholar 

  126. Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK Cells. Cell Metab. 24, 657–671 (2016).

    CAS  PubMed  Google Scholar 

  127. Cong, J. et al. Dysfunction of natural killer cells by FBP1-induced inhibition of glycolysis during lung cancer progression. Cell Metab. 28, 243–255 (2018).

    CAS  PubMed  Google Scholar 

  128. O’Brien, K. L. & Finlay, D. K. Immunometabolism and natural killer cell responses. Nat. Rev. Immunol. 19, 282–290 (2019).

    PubMed  Google Scholar 

  129. Clift, R., Souratha, J., Garrovillo, S. A., Zimmerman, S. & Blouw, B. Remodeling the tumor microenvironment sensitizes breast tumors to anti-programmed death-ligand 1 immunotherapy. Cancer Res. 79, 4149–4159 (2019).

    CAS  PubMed  Google Scholar 

  130. Condiotti, R., Zakai, Y. B., Barak, V. & Nagler, A. Ex vivo expansion of CD56+cytotoxic cells from human umbilical cord blood. Exp. Hematol. 29, 104–113 (2001).

    CAS  PubMed  Google Scholar 

  131. Tomchuck, S. L., Leung, W. H. & Dallas, M. H. Enhanced cytotoxic function of natural killer and CD3+CD56+ cells in cord blood after culture. Biol. Blood Marrow Transplant. 21, 39–49 (2015).

    CAS  PubMed  Google Scholar 

  132. Liu, E. et al. 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 (2018).

    CAS  PubMed  Google Scholar 

  133. Kang, L. et al. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. Front. Immunol. 4, 101 (2013).

    PubMed  PubMed Central  Google Scholar 

  134. Tam, Y. K., Martinson, J. A., Doligosa, K. & Klingemann, H. G. Ex vivo expansion of the highly cytotoxic human natural killer-92 cell-line under current good manufacturing practice conditions for clinical adoptive cellular immunotherapy. Cytotherapy 5, 259–272 (2003).

    CAS  PubMed  Google Scholar 

  135. Shimasaki, N., Coustan-Smith, E., Kamiya, T. & Campana, D. Expanded and armed natural killer cells for cancer treatment. Cytotherapy 18, 1422–1434 (2016).

    CAS  PubMed  Google Scholar 

  136. Lee, D. A., Verneris, M. R. & Campana, D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. Methods Mol. Biol. 651, 61–77 (2010).

    CAS  PubMed  Google Scholar 

  137. Williams, S. M. et al. Clinical-scale production of cGMP compliant CD3/CD19 cell-depleted NK cells in the evolution of NK cell immunotherapy at a single institution. Transfusion 58, 1458–1467 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Ettinghausen, S. E. et al. Hematologic effects of immunotherapy with lymphokine-activated killer cells and recombinant interleukin-2 in cancer patients. Blood 69, 1654–1660 (1987).

    CAS  PubMed  Google Scholar 

  139. Grimm, E. A. et al. Lymphokine-activated killer cell phenomenon. III. Evidence that IL-2 is sufficient for direct activation of peripheral blood lymphocytes into lymphokine-activated killer cells. J. Exp. Med. 158, 1356–1361 (1983).

    CAS  PubMed  Google Scholar 

  140. Phillips, J. H. & Lanier, L. L. Dissection of the lymphokine-activated killer phenomenon. Relative contribution of peripheral blood natural killer cells and T lymphocytes to cytolysis. J. Exp. Med. 164, 814–825 (1986).

    CAS  PubMed  Google Scholar 

  141. James, A. M. et al. Rapid activation receptor- or IL-2-induced lytic granule convergence in human natural killer cells requires Src, but not downstream signaling. Blood 121, 2627–2637 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. van Ostaijen-ten Dam, M. M. et al. Preparation of cytokine-activated NK cells for use in adoptive cell therapy in cancer patients: protocol optimization and therapeutic potential. J. Immunother. 39, 90–100 (2016).

    PubMed  Google Scholar 

  143. Mao, Y. et al. IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells. Blood 128, 1475–1489 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Felices, M. et al. Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect. JCI Insight 3, 96219 (2018).

    PubMed  Google Scholar 

  145. Leong, J. W. et al. Preactivation with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells. Biol. Blood Marrow Transplant. 20, 463–473 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Romee, R. et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci. Transl Med. 8, 357ra123 (2016). This article provides an extensive description of the features of memory-like NK cells obtained after activation with IL-12, IL-15 and IL-18, and their application to treat patients with AML.

    PubMed  PubMed Central  Google Scholar 

  147. Cichocki, F. et al. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. Cancer Res. 77, 5664–5675 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Spanholtz, J. et al. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. PLOS ONE 6, e20740 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Knorr, D. A. et al. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Stem Cell Transl. Med. 2, 274–283 (2013).

    CAS  Google Scholar 

  150. Li, Y., Hermanson, D. L., Moriarity, B. S. & Kaufman, D. S. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell 23, 181–192 (2018). This article is the first to demonstrate that CAR NK cells can be derived from iPSCs expressing CAR.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Denman, C. J. et al. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLOS ONE 7, e30264 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Robertson, M. J., Manley, T. J., Donahue, C., Levine, H. & Ritz, J. Costimulatory signals are required for optimal proliferation of human natural killer cells. J. Immunol. 150, 1705–1714 (1993).

    CAS  PubMed  Google Scholar 

  153. Alici, E. et al. Autologous antitumor activity by NK cells expanded from myeloma patients using GMP-compliant components. Blood 111, 3155–3162 (2008).

    CAS  PubMed  Google Scholar 

  154. Harada, H., Watanabe, S., Saijo, K., Ishiwata, I. & Ohno, T. A Wilms tumor cell line, HFWT, can greatly stimulate proliferation of CD56+ human natural killer cells and their novel precursors in blood mononuclear cells. Exp. Hematol 32, 614–621 (2004).

    PubMed  Google Scholar 

  155. Parkhurst, M. R., Riley, J. P., Dudley, M. E. & Rosenberg, S. A. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin. Cancer Res. 17, 6287–6297 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 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).

    PubMed  Google Scholar 

  157. Berg, M. et al. Clinical-grade ex vivo-expanded human natural killer cells up-regulate activating receptors and death receptor ligands and have enhanced cytolytic activity against tumor cells. Cytotherapy 11, 341–355 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Granzin, M. et al. Highly efficient IL-21 and feeder cell-driven ex vivo expansion of human NK cells with therapeutic activity in a xenograft mouse model of melanoma. Oncoimmunology 5, e1219007 (2016).

    PubMed  PubMed Central  Google Scholar 

  159. Phillips, J. H. & Lanier, L. L. A model for the differentiation of human natural killer cells. Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562. J. Exp. Med. 161, 1464–1482 (1985).

    CAS  PubMed  Google Scholar 

  160. Lapteva, N. et al. Large-scale ex vivo expansion and characterization of natural killer cells for clinical applications. Cytotherapy 14, 1131–1143 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Shah, N. N. et al. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation. Blood 125, 784–792 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Ciurea, S. O. et al. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Blood 130, 1857–1868 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Kweon, S. et al. Expansion of human NK cells using K562 cells expressing OX40 ligand and short exposure to IL-21. Front. Immunol. 10, 879 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Kottaridis, P. D. et al. Two-stage priming of allogeneic natural killer cells for the treatment of patients with acute myeloid leukemia: a phase I trial. PLOS ONE 10, e0123416 (2015).

    PubMed  PubMed Central  Google Scholar 

  165. Oyer, J. L. et al. Generation of highly cytotoxic natural killer cells for treatment of acute myelogenous leukemia using a feeder-free, particle-based approach. Biol. Blood Marrow Transplant. 21, 632–639 (2015).

    CAS  PubMed  Google Scholar 

  166. Oyer, J. L. et al. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. Cytotherapy 18, 653–663 (2016).

    CAS  PubMed  Google Scholar 

  167. Miller, J. S. et al. Expansion and homing of adoptively transferred human natural killer cells in immunodeficient mice varies with product preparation and in vivo cytokine administration: implications for clinical therapy. Biol. Blood Marrow Transplant. 20, 1252–1257 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Shimasaki, N. et al. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. Cytotherapy 14, 830–840 (2012).

    CAS  PubMed  Google Scholar 

  169. Shimasaki, N. & Campana, D. Natural killer cell reprogramming with chimeric immune receptors. Methods Mol. Biol. 969, 203–220 (2013).

    CAS  PubMed  Google Scholar 

  170. Wu, J. et al. An activating immunoreceptor complex formed by NKG2D and DAP10. Science 285, 730–732 (1999).

    CAS  PubMed  Google Scholar 

  171. Garrity, D., Call, M. E., Feng, J. & Wucherpfennig, K. W. The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure. Proc. Natl Acad. Sci. USA 102, 7641–7646 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 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). This article describes how genetic engineering of activated NK cells expressing a NKG2D chimeric receptor markedly enhances their antitumour activity.

    CAS  PubMed  Google Scholar 

  173. Kamiya, T., Chang, Y. H. & Campana, D. Expanded and activated natural killer cells for immunotherapy of hepatocellular carcinoma. Cancer Immunol. Res. 4, 574–581 (2016).

    CAS  PubMed  Google Scholar 

  174. Parihar, R. et al. NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. Cancer Immunol. Res. 7, 363–375 (2019). This article demonstrates that NK cells armed with an NKG2D chimeric receptor can increase the activity of CAR T cells in solid tumours through killing of myeloid-derived suppressor cells.

    PubMed  PubMed Central  Google Scholar 

  175. Imai, C. et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18, 676–684 (2004).

    CAS  PubMed  Google Scholar 

  176. Kruschinski, A. et al. Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas. Proc. Natl Acad. Sci. USA 105, 17481–17486 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Han, J. et al. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. Sci. Rep. 5, 11483 (2015).

    PubMed  PubMed Central  Google Scholar 

  178. 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).

    CAS  PubMed  Google Scholar 

  179. Altvater, B. et al. 2B4 (CD244) signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells. Clin. Cancer Res. 15, 4857–4866 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Muller, N. et al. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma. J. Immunother. 38, 197–210 (2015).

    PubMed  PubMed Central  Google Scholar 

  181. Zhang, C. et al. 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 (2017).

    PubMed  PubMed Central  Google Scholar 

  182. Walseng, E. et al. A TCR-based chimeric antigen receptor. Sci. Rep. 7, 10713 (2017).

    PubMed  PubMed Central  Google Scholar 

  183. Rosenberg, S. A. et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N. Engl. J. Med. 316, 889–897 (1987).

    CAS  PubMed  Google Scholar 

  184. Burns, L. J. et al. IL-2-based immunotherapy after autologous transplantation for lymphoma and breast cancer induces immune activation and cytokine release: a phase I/II trial. Bone Marrow Transplant. 32, 177–186 (2003).

    CAS  PubMed  Google Scholar 

  185. Giebel, S. et al. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood 102, 814–819 (2003).

    CAS  PubMed  Google Scholar 

  186. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Bachanova, V. et al. Donor KIR B genotype improves progression-free survival of non-Hodgkin lymphoma patients receiving unrelated donor transplantation. Biol. Blood Marrow Transplant. 22, 1602–1607 (2016).

    PubMed  PubMed Central  Google Scholar 

  189. Cichocki, F. et al. CD56dimCD57+NKG2C+ NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT. Leukemia 30, 456–463 (2016).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Cooley, S. et al. Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia. Blood 113, 726–732 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Muller, S. et al. Definition of a critical T cell threshold for prevention of GVHD after HLA non-identical PBPC transplantation in children. Bone Marrow Transplant. 24, 575–581 (1999).

    CAS  PubMed  Google Scholar 

  193. Dolstra, H. et al. Successful transfer of umbilical cord blood CD34+ hematopoietic stem and progenitor-derived NK cells in older acute myeloid leukemia patients. Clin. Cancer Res. 23, 4107–4118 (2017).

    CAS  PubMed  Google Scholar 

  194. Grzywacz, B. et al. Natural killer cell homing and persistence in the bone marrow after adoptive immunotherapy correlates with better leukemia control. J. Immunother. 42, 65–72 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Bjorklund, A. T. et al. Complete remission with reduction of high-risk clones following haploidentical NK-cell therapy against MDS and AML. Clin. Cancer Res. 24, 1834–1844 (2018).

    CAS  PubMed  Google Scholar 

  196. Williams, R. L. et al. Recipient T cell exhaustion and successful adoptive transfer of haploidentical natural killer cells. Biol. Blood Marrow Transplant. 24, 618–622 (2018).

    CAS  PubMed  Google Scholar 

  197. Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12, 269–281 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Knorr, D. A., Bachanova, V., Verneris, M. R. & Miller, J. S. Clinical utility of natural killer cells in cancer therapy and transplantation. Semin. Immunol. 26, 161–172 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Curti, A. et al. Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. Blood 118, 3273–3279 (2011).

    CAS  PubMed  Google Scholar 

  200. Bachanova, V. et al. Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. Blood 123, 3855–3863 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Nguyen, R. et al. A phase II clinical trial of adoptive transfer of haploidentical natural killer cells for consolidation therapy of pediatric acute myeloid leukemia. J. Immunother. Cancer 7, 81 (2019).

    PubMed  PubMed Central  Google Scholar 

  202. Szmania, S. et al. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. J. Immunother. 38, 24–36 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 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).

    CAS  PubMed  Google Scholar 

  204. Federico, S. M. et al. A pilot trial of humanized anti-GD2 monoclonal antibody (hu14.18K322A) with chemotherapy and natural killer cells in children with recurrent/refractory neuroblastoma. Clin. Cancer Res. 23, 6441–6449 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Modak, S. et al. Adoptive immunotherapy with haploidentical natural killer cells and Anti-GD2 monoclonal antibody m3F8 for resistant neuroblastoma: Results of a phase I study. Oncoimmunology 7, e1461305 (2018).

    PubMed  PubMed Central  Google Scholar 

  206. Bachanova, V. et al. Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells. Cancer Immunol. Immunother. 67, 483–494 (2018).

    CAS  PubMed  Google Scholar 

  207. Campana, D. & Pui, C. H. Detection of minimal residual disease in acute leukemia: methodologic advances and clinical significance. Blood 85, 1416–1434 (1995).

    CAS  PubMed  Google Scholar 

  208. Brudno, J. N. & Kochenderfer, J. N. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 127, 3321–3330 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Torikai, H. et al. Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood 122, 1341–1349 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Valton, J. et al. A multidrug-resistant engineered car t cell for allogeneic combination immunotherapy. Mol. Ther. 23, 1507–1518 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Freud, A. G., Mundy-Bosse, B. L., Yu, J. & Caligiuri, M. A. The broad spectrum of human natural killer cell diversity. Immunity 47, 820–833 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Crinier, A. et al. High-dimensional single-cell analysis identifies organ-specific signatures and conserved NK cell subsets in humans and mice. Immunity 49, 971–986 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Collins, P. L. et al. Gene regulatory programs conferring phenotypic identities to human NK cells. Cell 176, 348–360 (2019). This article provides a comprehensive ‘omics’ analysis of human NK cell populations.

    CAS  PubMed  Google Scholar 

  214. Campana, D., Schwarz, H. & Imai, C. 4-1BB chimeric antigen receptors. Cancer J. 20, 134–140 (2014).

    CAS  PubMed  Google Scholar 

  215. Kudo, K. et al. T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing. Cancer Res. 74, 93–103 (2014).

    CAS  PubMed  Google Scholar 

  216. Ruscetti, M. et al. NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science 362, 1416–1422 (2018). This article reports that agents that induce senescence in tumour cells can promote NK cell surveillance through cytokine and chemokine secretion, and expression of activating ligands.

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Romee, R. et al. First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood 131, 2515–2527 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Margolin, K. et al. Phase I trial of ALT-803, a novel recombinant IL15 complex, in patients with advanced solid tumors. Clin. Cancer Res. 24, 5552–5561 (2018).

    PubMed  PubMed Central  Google Scholar 

  219. Davis, Z. B., Vallera, D. A., Miller, J. S. & Felices, M. Natural killer cells unleashed: Checkpoint receptor blockade and BiKE/TriKE utilization in NK-mediated anti-tumor immunotherapy. Semin. Immunol. 31, 64–75 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Felices, M. et al. Novel CD19-targeted TriKE restores NK cell function and proliferative capacity in CLL. Blood Adv. 3, 897–907 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Gauthier, L. et al. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. Cell 177, 1701–1713 (2019).

    CAS  PubMed  Google Scholar 

  223. Chester, C., Sanmamed, M. F., Wang, J. & Melero, I. Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood 131, 49–57 (2018).

    CAS  PubMed  Google Scholar 

  224. Segal, N. H. et al. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin. Cancer Res. 23, 1929–1936 (2017).

    CAS  PubMed  Google Scholar 

  225. Segal, N. H. et al. Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin. Cancer Res. 24, 1816–1823 (2018).

    CAS  PubMed  Google Scholar 

  226. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Vey, N. et al. A phase 1 trial of the anti-inhibitory KIR mAb IPH2101 for AML in complete remission. Blood 120, 4317–4323 (2012).

    CAS  PubMed  Google Scholar 

  229. Benson, D. M. Jr. et al. A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma. Blood 120, 4324–4333 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Ruggeri, L. et al. Effects of anti-NKG2A antibody administration on leukemia and normal hematopoietic cells. Haematologica 101, 626–633 (2015).

    PubMed  Google Scholar 

  231. Muntasell, A. et al. Targeting NK-cell checkpoints for cancer immunotherapy. Curr. Opin. Immunol. 45, 73–81 (2017).

    CAS  PubMed  Google Scholar 

  232. 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 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Brandt, C. S. et al. The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. J. Exp. Med. 206, 1495–1503 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. 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).

    CAS  PubMed  Google Scholar 

  235. Niehrs, A. et al. A subset of HLA-DP molecules serve as ligands for the natural cytotoxicity receptor NKp44. Nat. Immunol. 20, 1129–1137 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Zhang, Z. et al. DNAM-1 controls NK cell activation via an ITT-like motif. J. Exp. Med. 212, 2165–2182 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Eissmann, P. et al. Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244). Blood 105, 4722–4729 (2005).

    CAS  PubMed  Google Scholar 

  238. Arch, R. H. & Thompson, C. B. 4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor kappaB. Mol. Cell Biol. 18, 558–565 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Carretero, M. et al. The CD94 and NKG2-A C-type lectins covalently assemble to form a natural killer cell inhibitory receptor for HLA class I molecules. Eur. J. Immunol. 27, 563–567 (1997).

    CAS  PubMed  Google Scholar 

  240. Gornalusse, G. G. et al. HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells. Nat. Biotechnol. 35, 765–772 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Borrego, F. et al. Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells. Mol. Immunol. 38, 637–660 (2002).

    CAS  PubMed  Google Scholar 

  242. Kaiser, B. K., Pizarro, J. C., Kerns, J. & Strong, R. K. Structural basis for NKG2A/CD94 recognition of HLA-E. Proc. Natl Acad. Sci. USA 105, 6696–6701 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Martinet, L. & Smyth, M. J. Balancing natural killer cell activation through paired receptors. Nat. Rev. Immunol. 15, 243–254 (2015).

    CAS  PubMed  Google Scholar 

  244. Passweg, J. R. et al. Purified donor NK-lymphocyte infusion to consolidate engraftment after haploidentical stem cell transplantation. Leukemia 18, 1835–1838 (2004).

    CAS  PubMed  Google Scholar 

  245. Shaffer, B. C. et al. Phase II study of haploidentical natural killer cell infusion for treatment of relapsed or persistent myeloid malignancies following allogeneic hematopoietic cell transplantation. Biol. Blood Marrow Transplant. 22, 705–709 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank the National Medical Research Council of Singapore (grant NMRC/STaR/0025/2015), the Goh Foundation and the VIVA Foundation for Children with Cancer for their support.

Author information

Authors and Affiliations

Authors

Contributions

All authors researched data for article, substantially contributed to discussion of the content and reviewed and edited the manuscript before submission. D.C. wrote the article.

Corresponding author

Correspondence to Dario Campana.

Ethics declarations

Competing interests

D.C. has received patent royalties from Juno Therapeutics (a Celgene company), Unum Therapeutics, Nkarta Therapeutics and Medisix Therapeutics; he is a co-founder of, stockholder of and consultant for Unum, Nkarta and Medisix. N.S. and D.C. are co-inventors on patent applications licensed to Nkarta or unlicensed. A.J. has no financial competing interests. None of the authors has non-financial competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Graft-versus-host disease

(GVHD). A condition resulting from the systemic attack of allogenic T cells on the tissues of an immunosuppressed recipient, which, in its most severe grade, is fatal. It can occur after allogeneic haematopoietic stem cell transplantation or after infusion of allogeneic T cells.

Killer cell immunoglobulin-like receptors

(KIRs). Transmembrane proteins expressed by natural killer (NK) cells that interact with major histocompatibility complex/human leukocyte antigen class I molecules to modulate NK cell cytotoxicity by delivery predominantly inhibitory signals. KIR signalling during NK cell development is important for NK cell functional competency or licensing.

Licensing

A process driven by the interaction between inhibitory receptors on maturing natural killer cells and self-major histocompatibility complex molecules which increases natural killer cell responses to activating receptor signals.

Anergic

A hypofunctional state. In natural killer cells, anergy or hyporesponsiveness to activating signals might be caused by chronic stimulation during maturation through an activating receptor interacting with a self-ligand.

K562 cells

A chronic myelogenous leukaemia cell line that expresses the BCR–ABL1 fusion gene, which lacks major histocompatibility complex/human leukocyte antigen surface expression and is commonly used as a target in natural killer (NK) cell cytotoxicity assays. Contact with K562 activates NK cells, K562 cells modified to express cytokines and stimulatory molecules are used to stimulate NK cell proliferation.

Leukapheresis

A procedure that removes white blood cells from blood,while returning the remainder blood components to circulation. A leukapheresis product is often used as a starting material to obtain peripheral blood natural killer cells.

Lymphokine-activated killer cells

(LAK cells). Lymphocytes obtained from cancer patients, incubated with cytokines, such as IL-2, and then reinfused into patients with therapeutic intent, often in conjunction with IL-2.

Vascular leak syndrome

A serious clinical condition characterized by increased vascular permeability accompanied by the escape of plasma through capillary walls. It is most commonly seen in sepsis, and it is one of the major dose-limiting toxic effects of IL-2.

Minimal residual disease

Leukaemic cells undetectable by conventional morphological techniques but detectable by flow cytometry or molecular methods in peripheral blood or bone marrow. Contemporary minimal residual disease assays can detect one leukaemic cell among 10,000 or more normal cells.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shimasaki, N., Jain, A. & Campana, D. NK cells for cancer immunotherapy. Nat Rev Drug Discov 19, 200–218 (2020). https://doi.org/10.1038/s41573-019-0052-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41573-019-0052-1

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing