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:

Targeting natural killer cells in cancer immunotherapy

Abstract

Alteration in the expression of cell-surface proteins is a common consequence of malignant transformation. Natural killer (NK) cells use an array of germline-encoded activating and inhibitory receptors that scan for altered protein-expression patterns, but tumor evasion of detection by the immune system is now recognized as one of the hallmarks of cancer. NK cells display rapid and potent immunity to metastasis or hematological cancers, and major efforts are now being undertaken to fully exploit NK cell anti-tumor properties in the clinic. Diverse approaches encompass the development of large-scale NK cell–expansion protocols for adoptive transfer, the establishment of a microenvironment favorable to NK cell activity, the redirection of NK cell activity against tumor cells and the release of inhibitory signals that limit NK cell function. In this Review we detail recent advances in NK cell–based immunotherapies and discuss the advantages and limitations of these strategies.

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

Figure 1: Various approaches to therapy with the adoptive transfer of NK cells.
Figure 2: Targeting the tumor microenvironment to improve NK cell responses.
Figure 3: Therapeutic approaches that engage activating receptors on NK cells.
Figure 4: Checkpoint inhibitors that 'release' NK cell functions.

Similar content being viewed by others

References

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

    CAS  PubMed  Google Scholar 

  2. Huntington, N.D., Vosshenrich, C.A. & Di Santo, J.P. Developmental pathways that generate natural-killer-cell diversity in mice and humans. Nat. Rev. Immunol. 7, 703–714 (2007).

    CAS  PubMed  Google Scholar 

  3. Hayakawa, Y., Huntington, N.D., Nutt, S.L. & Smyth, M.J. Functional subsets of mouse natural killer cells. Immunol. Rev. 214, 47–55 (2006).

    CAS  PubMed  Google Scholar 

  4. Martinet, L. et al. DNAM-1 expression marks an alternative program of NK cell maturation. Cell Rep. 11, 85–97 (2015).

    CAS  PubMed  Google Scholar 

  5. Sojka, D.K., Tian, Z. & Yokoyama, W.M. Tissue-resident natural killer cells and their potential diversity. Semin. Immunol. 26, 127–131 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Cortez, V.S., Fuchs, A., Cella, M., Gilfillan, S. & Colonna, M. Cutting edge: Salivary gland NK cells develop independently of Nfil3 in steady-state. J. Immunol. 192, 4487–4491 (2014).

    CAS  PubMed  Google Scholar 

  7. Marquardt, N. et al. Cutting edge: identification and characterization of human intrahepatic CD49a+ NK cells. J. Immunol. 194, 2467–2471 (2015).

    CAS  PubMed  Google Scholar 

  8. Spits, H. et al. Innate lymphoid cells--a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  10. Romee, R., Leong, J.W. & Fehniger, T.A. Utilizing cytokines to function-enable human NK cells for the immunotherapy of cancer. Scientifica (Cairo) 2014, 205796 (2014).

    PubMed Central  Google Scholar 

  11. Guillerey, C. et al. Toll-like receptor 3 regulates NK cell responses to cytokines and controls experimental metastasis. OncoImmunology 4, e1027468 (2015).

    PubMed  PubMed Central  Google Scholar 

  12. Voskoboinik, I., Smyth, M.J. & Trapani, J.A. Perforin-mediated target-cell death and immune homeostasis. Nat. Rev. Immunol. 6, 940–952 (2006).

    CAS  PubMed  Google Scholar 

  13. Sungur, C.M. & Murphy, W.J. Positive and negative regulation by NK cells in cancer. Crit. Rev. Oncog. 19, 57–66 (2014).

    PubMed  PubMed Central  Google Scholar 

  14. Iannello, A., Thompson, T.W., Ardolino, M., Lowe, S.W. & Raulet, D.H. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J. Exp. Med. 210, 2057–2069 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Guillerey, C. & Smyth, M.J. NK cells and cancer immunoediting. Curr. Top. Microbiol. Immunol. 395, 115–145 (2016).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  17. Krasnova, Y., Putz, E.M., Smyth, M.J. & Souza-Fonseca-Guimaraes, F. Bench to bedside: NK cells and control of metastasis. Clin. Immunol. S1521-6616(15)30050-4 (2015).

  18. Ghiringhelli, F. et al. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-β-dependent manner. J. Exp. Med. 202, 1075–1085 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Smyth, M.J. et al. CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. J. Immunol. 176, 1582–1587 (2006).

    CAS  PubMed  Google Scholar 

  20. Beavis, P.A. et al. Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc. Natl. Acad. Sci. USA 110, 14711–14716 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Mittal, D. et al. Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res. 74, 3652–3658 (2014).

    CAS  PubMed  Google Scholar 

  22. Stacey, M.A., Marsden, M., Wang, E.C., Wilkinson, G.W. & Humphreys, I.R. IL-10 restricts activation-induced death of NK cells during acute murine cytomegalovirus infection. J. Immunol. 187, 2944–2952 (2011).

    CAS  PubMed  Google Scholar 

  23. Mocellin, S. et al. IL-10 stimulatory effects on human NK cells explored by gene profile analysis. Genes Immun. 5, 621–630 (2004).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  25. Sconocchia, G. et al. Melanoma cells inhibit NK cell functions. Cancer Res. 72, 5428–5429 author reply 5430 (2012).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  27. 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 

  28. Grossenbacher, S.K., Canter, R.J. & Murphy, W.J. Natural killer cell immunotherapy to target stem-like tumor cells. J. Immunother. Cancer 4, 19 (2016).

    PubMed  PubMed Central  Google Scholar 

  29. Delgado, D.C. et al. Genotypes of NK cell KIR receptors, their ligands, and Fcγ receptors in the response of neuroblastoma patients to Hu14.18-IL2 immunotherapy. Cancer Res. 70, 9554–9561 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Yang, R.K. et al. Intratumoral treatment of smaller mouse neuroblastoma tumors with a recombinant protein consisting of IL-2 linked to the hu14.18 antibody increases intratumoral CD8+ T and NK cells and improves survival. Cancer Immunol. Immunother. 62, 1303–1313 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 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 

  32. Zhang, C. et al. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. J. Natl. Cancer Inst. 108, djv375 (2015).

    Google Scholar 

  33. Genßler, S. et al. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. OncoImmunology 5, e1119354 (2015).

    PubMed  PubMed Central  Google Scholar 

  34. Besse, B. et al. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. OncoImmunology 5, e1071008 (2015).

    PubMed  PubMed Central  Google Scholar 

  35. Tonn, T. et al. Treatment of patients with advanced cancer with the natural killer cell line NK-92. Cytotherapy 15, 1563–1570 (2013).

    CAS  PubMed  Google Scholar 

  36. Becker, P.S. et al. Selection and expansion of natural killer cells for NK cell-based immunotherapy. Cancer Immunol. Immunother. 65, 477–484 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 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 

  38. Rueff, J., Medinger, M., Heim, D., Passweg, J. & Stern, M. Lymphocyte subset recovery and outcome after autologous hematopoietic stem cell transplantation for plasma cell myeloma. Biol. Blood Marrow Transplant. 20, 896–899 (2014).

    PubMed  Google Scholar 

  39. Porrata, L.F. et al. Early lymphocyte recovery predicts superior survival after autologous stem cell transplantation in non-Hodgkin lymphoma: a prospective study. Biol. Blood Marrow Transplant. 14, 807–816 (2008).

    PubMed  PubMed Central  Google Scholar 

  40. Sakamoto, N. et al. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. J. Transl. Med. 13, 277 (2015). This study established a new expansion method for obtaining large numbers of functional NK cells from small quantities of blood. Expanded populations of autologous NK cells were safe to administer to patients with cancer, and this led to enhanced cytotoxic activity against NK cell targets.

    PubMed  PubMed Central  Google Scholar 

  41. 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 

  42. 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 

  43. Miller, J.S. et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 105, 3051–3057 (2005).

    CAS  PubMed  Google Scholar 

  44. 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 

  45. 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 

  46. Bishara, A. et al. The beneficial role of inhibitory KIR genes of HLA class I NK epitopes in haploidentically mismatched stem cell allografts may be masked by residual donor-alloreactive T cells causing GVHD. Tissue Antigens 63, 204–211 (2004).

    CAS  PubMed  Google Scholar 

  47. Davies, S.M. et al. Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Killer immunoglobulin-like receptor. Blood 100, 3825–3827 (2002).

    CAS  PubMed  Google Scholar 

  48. Gill, S. & June, C.H. Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies. Immunol. Rev. 263, 68–89 (2015).

    CAS  PubMed  Google Scholar 

  49. Klingemann, H. Are natural killer cells superior CAR drivers? OncoImmunology 3, e28147 (2014).

    PubMed  PubMed Central  Google Scholar 

  50. Glienke, W. et al. Advantages and applications of CAR-expressing natural killer cells. Front. Pharmacol. 6, 21 (2015).

    PubMed  PubMed Central  Google Scholar 

  51. Klingemann, H. Challenges of cancer therapy with natural killer cells. Cytotherapy 17, 245–249 (2015).

    CAS  PubMed  Google Scholar 

  52. Romanski, A. et al. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. J. Cell. Mol. Med. 20, 1287–1294 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Schönfeld, K. et al. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Mol. Ther. 23, 330–338 (2015). This study was the first to test the effect of irradiation (a necessary safety measure) on the anti-tumor activity of NK cell lines and demonstrated that irradiated NK cells expressing an anti-ErbB2 CAR protected mice against metastases.

    PubMed  Google Scholar 

  54. 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 

  55. 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 

  56. 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). This clinical trial report demonstrated the therapeutic benefit of eliminating T reg cells with an IL-2–diphtheria fusion protein before the infusion of haploidentical NK cells in patients with AML. This study provided evidence of the negative role of T reg cells on the population expansion of NK cells after transfer and proposed that the detection of donor NK cells 7 days after infusion could serve as a surrogate marker for a clinical response.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Steele, N. et al. A phase 1 trial of recombinant human IL-21 in combination with cetuximab in patients with metastatic colorectal cancer. Br. J. Cancer 106, 793–798 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Waldmann, T.A. Interleukin-15 in the treatment of cancer. Expert Rev. Clin. Immunol. 10, 1689–1701 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Porrata, L.F. et al. Interleukin-15 affects patient survival through natural killer cell recovery after autologous hematopoietic stem cell transplantation for non-Hodgkin lymphomas. Clin. Dev. Immunol. 2010, 914945 (2010).

    PubMed  PubMed Central  Google Scholar 

  60. 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). This study reported the first clinical trial in which recombinant IL-15 was administered to patients with metastatic cancer, which led to the clearance of lung lesions in two patients.

    CAS  PubMed  Google Scholar 

  61. Pérez-Martínez, A. et al. A phase I/II trial of interleukin-15--stimulated natural killer cell infusion after haplo-identical stem cell transplantation for pediatric refractory solid tumors. Cytotherapy 17, 1594–1603 (2015).

    PubMed  Google Scholar 

  62. Kim, P.S. et al. IL-15 superagonist/IL-15RαSushi-Fc fusion complex (IL-15SA/IL-15RαSu-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8+ T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas. Oncotarget 7, 16130–16145 (2016).

    PubMed  PubMed Central  Google Scholar 

  63. Sahm, C., Schönfeld, K. & Wels, W.S. Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor. Cancer Immunol. Immunother. 61, 1451–1461 (2012).

    CAS  PubMed  Google Scholar 

  64. Imamura, M. et al. Autonomous growth and increased cytotoxicity of natural killer cells expressing membrane-bound interleukin-15. Blood 124, 1081–1088 (2014).

    CAS  PubMed  Google Scholar 

  65. Krieg, S. & Ullrich, E. Novel immune modulators used in hematology: impact on NK cells. Front. Immunol. 3, 388 (2013).

    PubMed  PubMed Central  Google Scholar 

  66. Davies, F.E. et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 98, 210–216 (2001).

    CAS  PubMed  Google Scholar 

  67. Borg, C. et al. Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. J. Clin. Invest. 114, 379–388 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Parameswaran, R. et al. Repression of GSK3 restores NK cell cytotoxicity in AML patients. Nat. Commun. 7, 11154 (2016). This study identified the glycogen synthetase GSK3-β as an intrinsic inhibitor of NK cell responses in patients with AML. Small-molecule inhibitors of GSK3 increased the cytotoxicity of NK cells against AML cells and proved protective in a humanized mouse model of AML.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Schmiedel, B.J. et al. Azacytidine impairs NK cell reactivity while decitabine augments NK cell responsiveness toward stimulation. Int. J. Cancer 128, 2911–2922 (2011).

    CAS  PubMed  Google Scholar 

  70. Rossi, L.E. et al. Histone deacetylase inhibitors impair NK cell viability and effector functions through inhibition of activation and receptor expression. J. Leukoc. Biol. 91, 321–331 (2012).

    CAS  PubMed  Google Scholar 

  71. Jardine, L. et al. Sensitizing primary acute lymphoblastic leukemia to natural killer cell recognition by induction of NKG2D ligands. Leuk. Lymphoma 54, 167–173 (2013).

    CAS  PubMed  Google Scholar 

  72. Wang, X. et al. Proteasome inhibition induces apoptosis in primary human natural killer cells and suppresses NKp46-mediated cytotoxicity. Haematologica 94, 470–478 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Lundqvist, A., Yokoyama, H., Smith, A., Berg, M. & Childs, R. Bortezomib treatment and regulatory T-cell depletion enhance the antitumor effects of adoptively infused NK cells. Blood 113, 6120–6127 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Marçais, A. et al. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat. Immunol. 15, 749–757 (2014).

    PubMed  PubMed Central  Google Scholar 

  75. Weiner, L.M., Surana, R. & Wang, S. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat. Rev. Immunol. 10, 317–327 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Bakema, J.E. & van Egmond, M. Fc receptor-dependent mechanisms of monoclonal antibody therapy of cancer. Curr. Top. Microbiol. Immunol. 382, 373–392 (2014).

    CAS  PubMed  Google Scholar 

  77. Weng, W.K. & Levy, R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J. Clin. Oncol. 21, 3940–3947 (2003).

    CAS  PubMed  Google Scholar 

  78. Rodríguez, J. et al. Fc gamma receptor polymorphisms as predictive markers of Cetuximab efficacy in epidermal growth factor receptor downstream-mutated metastatic colorectal cancer. Eur. J. Cancer 48, 1774–1780 (2012).

    PubMed  Google Scholar 

  79. Clynes, R.A., Towers, T.L., Presta, L.G. & Ravetch, J.V. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat. Med. 6, 443–446 (2000).

    CAS  PubMed  Google Scholar 

  80. Gluck, W.L. et al. Phase I studies of interleukin (IL)-2 and rituximab in B-cell non-Hodgkin's lymphoma: IL-2 mediated natural killer cell expansion correlations with clinical response. Clin. Cancer Res. 10, 2253–2264 (2004).

    CAS  PubMed  Google Scholar 

  81. Romee, R. et al. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood 121, 3599–3608 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Zhou, Q., Gil-Krzewska, A., Peruzzi, G. & Borrego, F. Matrix metalloproteinases inhibition promotes the polyfunctionality of human natural killer cells in therapeutic antibody-based anti-tumour immunotherapy. Clin. Exp. Immunol. 173, 131–139 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Bowles, J.A. et al. Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab. Blood 108, 2648–2654 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Gerdes, C.A. et al. GA201 (RG7160): a novel, humanized, glycoengineered anti-EGFR antibody with enhanced ADCC and superior in vivo efficacy compared with cetuximab. Clin. Cancer Res. 19, 1126–1138 (2013).

    CAS  PubMed  Google Scholar 

  85. Roberti, M.P. et al. IL-2- or IL-15-activated NK cells enhance cetuximab-mediated activity against triple-negative breast cancer in xenografts and in breast cancer patients. Breast Cancer Res. Treat. 136, 659–671 (2012).

    CAS  PubMed  Google Scholar 

  86. Moga, E. et al. NK cells stimulated with IL-15 or CpG ODN enhance rituximab-dependent cellular cytotoxicity against B-cell lymphoma. Exp. Hematol. 36, 69–77 (2008).

    CAS  PubMed  Google Scholar 

  87. Wu, L. et al. lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin. Cancer Res. 14, 4650–4657 (2008).

    CAS  PubMed  Google Scholar 

  88. Gleason, M.K. et al. Bispecific and trispecific killer cell engagers directly activate human NK cells through CD16 signaling and induce cytotoxicity and cytokine production. Mol. Cancer Ther. 11, 2674–2684 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Hartmann, F. et al. Treatment of refractory Hodgkin's disease with an anti-CD16/CD30 bispecific antibody. Blood 89, 2042–2047 (1997).

    CAS  PubMed  Google Scholar 

  90. Shahied, L.S. et al. Bispecific minibodies targeting HER2/neu and CD16 exhibit improved tumor lysis when placed in a divalent tumor antigen binding format. J. Biol. Chem. 279, 53907–53914 (2004).

    CAS  PubMed  Google Scholar 

  91. Wiernik, A. et al. Targeting natural killer cells to acute myeloid leukemia in vitro with a CD16 x 33 bispecific killer cell engager and ADAM17 inhibition. Clin. Cancer Res. 19, 3844–3855 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Schmohl, J.U., Gleason, M.K., Dougherty, P.R., Miller, J.S. & Vallera, D.A. Heterodimeric bispecific single chain variable fragments (scFv) killer engagers (BiKEs) enhance NK-cell activity against CD133+ colorectal cancer cells. Target. Oncol. (2015). This paper reported the design of a '16x133' bispecific killer-cell engager that directs NK cell cytotoxic activity against CD133-expressing cancer cells. This has important therapeutic potential given its ability to target the drug-resistant cancer stem cell population that is CD133+ in many cancers.

  93. 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. (2016). This study reports the generation of IL-15 trispecific killer-cell engagers with stable integration of IL-15 into a bispecific antibody platform that recognizes CD16 on NK cells and CD33 on myeloid cancer cells. The IL-15 linker incorporated into this construct sustained the survival and proliferation NK cells and demonstrated antitumor activity in a leukemia xenograft model.

  94. Boltz, A. et al. Bi-specific aptamers mediating tumor cell lysis. J. Biol. Chem. 286, 21896–21905 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Kellner, C. et al. Fusion proteins between ligands for NKG2D and CD20-directed single-chain variable fragments sensitize lymphoma cells for natural killer cell-mediated lysis and enhance antibody-dependent cellular cytotoxicity. Leukemia 26, 830–834 (2012).

    CAS  PubMed  Google Scholar 

  96. von Strandmann, E.P. et al. A novel bispecific protein (ULBP2-BB4) targeting the NKG2D receptor on natural killer (NK) cells and CD138 activates NK cells and has potent antitumor activity against human multiple myeloma in vitro and in vivo. Blood 107, 1955–1962 (2006).

    PubMed  Google Scholar 

  97. 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 

  98. Deng, W. et al. Antitumor immunity. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection. Science 348, 136–139 (2015). This was the first report showing a positive effect of a shed NKG2D ligand on the activation of NK cells. It demonstrated that MULT1, which binds with high affinity to NKG2D, stimulated NK cells and caused tumor rejection in mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Lanier, L.L. NKG2D receptor and its ligands in host defense. Cancer Immunol. Res. 3, 575–582 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 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 

  101. 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 

  102. Semeraro, M. et al. Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients. Sci. Transl. Med. 7, 283ra55 (2015).

    PubMed  Google Scholar 

  103. Viaud, S. et al. Dendritic cell-derived exosomes promote natural killer cell activation and proliferation: a role for NKG2D ligands and IL-15Ralpha. PLoS One 4, e4942 (2009).

    PubMed  PubMed Central  Google Scholar 

  104. Guillerey, C. et al. Immunosurveillance and therapy of multiple myeloma are CD226 dependent. J. Clin. Invest. 125, 2077–2089 (2015).

    PubMed  PubMed Central  Google Scholar 

  105. Chan, C.J. et al. DNAM-1/CD155 interactions promote cytokine and NK cell-mediated suppression of poorly immunogenic melanoma metastases. J. Immunol. 184, 902–911 (2010).

    CAS  PubMed  Google Scholar 

  106. Makkouk, A., Chester, C. & Kohrt, H.E. Rationale for anti-CD137 cancer immunotherapy. Eur. J. Cancer 54, 112–119 (2016).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  108. Kohrt, H.E. et al. CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies. Blood 117, 2423–2432 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Kohrt, H.E. et al. Targeting CD137 enhances the efficacy of cetuximab. J. Clin. Invest. 124, 2668–2682 (2014). This report established the synergistic effect of cetuximab (mAb to EGFR) and stimulation of CD137 in promoting the activation of human NK cells and protecting mice against tumors in various xenograft models. This work supports the development of clinical trials combining cetuximab with agonist mAb to CD137.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Sanmamed, M.F. et al. Agonists of co-stimulation in cancer immunotherapy directed against CD137, OX40, GITR, CD27, CD28, and ICOS. Semin. Oncol. 42, 640–655 (2015).

    CAS  PubMed  Google Scholar 

  111. Romagné, 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).

    PubMed  PubMed Central  Google Scholar 

  112. 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 

  113. 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). References 112 and 113 reported the first clinical trial of IPH2101, the antibody to human KIRs, in elderly patients with AML and patients with relapsed or refractory multiple myeloma.

    CAS  PubMed  Google Scholar 

  114. Korde, N. et al. A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma. Haematologica 99, e81–e83 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Kohrt, H.E. et al. Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies. Blood 123, 678–686 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Wieten, L., Mahaweni, N.M., Voorter, C.E., Bos, G.M. & Tilanus, M.G. Clinical and immunological significance of HLA-E in stem cell transplantation and cancer. Tissue Antigens 84, 523–535 (2014).

    CAS  PubMed  Google Scholar 

  117. Nguyen, S. et al. HLA-E upregulation on IFN-γ-activated AML blasts impairs CD94/NKG2A-dependent NK cytolysis after haplo-mismatched hematopoietic SCT. Bone Marrow Transplant. 43, 693–699 (2009).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  119. Chan, C.J. et al. The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions. Nat. Immunol. 15, 431–438 (2014).

    CAS  PubMed  Google Scholar 

  120. Blake, S.J. et al. Suppression of metastases using a new lymphocyte checkpoint target for cancer immunotherapy. Cancer Discov. 6, 446–459 (2016). This study defined a role for the immunoglobulin family receptor CD96 in inhibiting NK cell–mediated control of tumor metastases. Pre-clinical mouse models were used to establish the anti-metastatic activity of an antibody to CD96 as a single agent or in combination with conventional checkpoint inhibitors.

    CAS  PubMed  Google Scholar 

  121. Lesokhin, A.M., Callahan, M.K., Postow, M.A. & Wolchok, J.D. On being less tolerant: enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T cell activation. Sci. Transl. Med. 7, 280sr1 (2015).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  123. Huang, B.Y. et al. The PD-1/B7-H1 pathway modulates the natural killer cells versus mouse glioma stem cells. PLoS One 10, e0134715 (2015).

    PubMed  PubMed Central  Google Scholar 

  124. Westin, J.R. et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol. 15, 69–77 (2014).

    CAS  PubMed  Google Scholar 

  125. da Silva, I.P. et al. Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunol. Res. 2, 410–422 (2014).

    PubMed  PubMed Central  Google Scholar 

  126. Xu, L. et al. Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma. Int. Immunopharmacol. 29, 635–641 (2015).

    CAS  PubMed  Google Scholar 

  127. Wang, Z. et al. the clinical significance of abnormal Tim-3 expression on NK cells from patients with gastric cancer. Immunol. Invest. 44, 578–589 (2015).

    CAS  PubMed  Google Scholar 

  128. Nowak, J. et al. role of donor activating KIR-HLA ligand-mediated NK cell education status in control of malignancy in hematopoietic cell transplant recipients. Biol. Blood Marrow Transplant. 21, 829–839 (2015).

    CAS  PubMed  Google Scholar 

  129. Tarek, N. et al. Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment. J. Clin. Invest. 122, 3260–3270 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Zamora, A.E., Grossenbacher, S.K., Aguilar, E.G. & Murphy, W.J. Models to study NK cell biology and possible clinical application. Curr. Protoc. Immunol. 110, 11–14 (2015).

    Google Scholar 

  131. Huntington, N.D., Mention, J., Vosshenrich, C.A., Satoh-Takayama, N. & Di Santo, J.P. in Natural Killer Cells–at the Forefront of Modern Immunology 39–61 (Springer, 2010).

  132. Li, Y. & Di Santo, J.P. Probing human NK cell biology using human immune system (HIS) mice. Curr. Top. Microbiol. Immunol. 395, 191–208 (2016).

    CAS  PubMed  Google Scholar 

  133. Paolino, M. et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507, 508–512 (2014). This study highlighted the therapeutic potential of targeting the TAM–CBl-b inhibitory pathway in NK cells and demonstrated the anti-metastatic activity of newly developed small-molecule inhibitor of TAM kinase.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Putz, E.M. et al. CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance. Cell Rep. 4, 437–444 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Delconte, R.B. et al. CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nat. Immunol. 17, 816–824 (2016). This study identified CIS, the suppressor of IL-15 signaling in NK cells, as a potent checkpoint in NK cell activation. Deletion of CIS had a profound anti-metastastic effect in vivo , and adoptive therapy of CIS-null NK cells transferred resistance to melanoma metastasis.

    CAS  PubMed  Google Scholar 

  136. Maghazachi, A.A. Role of chemokines in the biology of natural killer cells. Curr. Top. Microbiol. Immunol. 341, 37–58 (2010).

    CAS  PubMed  Google Scholar 

  137. Bernardini, G. & Santoni, A. The pathophysiological role of chemokines in the regulation of NK cell tissue homing. Crit. Rev. Oncog. 19, 77–90 (2014).

    PubMed  Google Scholar 

  138. Young, A., Mittal, D., Stagg, J. & Smyth, M.J. Targeting cancer-derived adenosine: new therapeutic approaches. Cancer Discov. 4, 879–888 (2014).

    CAS  PubMed  Google Scholar 

  139. Huntington, N.D. The unconventional expression of IL-15 and its role in NK cell homeostasis. Immunol. Cell Biol. 92, 210–213 (2014).

    CAS  PubMed  Google Scholar 

  140. Delconte, R.B. et al. The helix-loop-helix protein ID2 governs NK cell fate by tuning their sensitivity to interleukin-15. Immunity 44, 103–115 (2016).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Stanietsky, N. et al. Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR. Eur. J. Immunol. 43, 2138–2150 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Fuchs, A., Cella, M., Giurisato, E., Shaw, A.S. & Colonna, M. Cutting edge: CD96 (tactile) promotes NK cell-target cell adhesion by interacting with the poliovirus receptor (CD155). J. Immunol. 172, 3994–3998 (2004).

    CAS  PubMed  Google Scholar 

  144. Jones, B.S., Lamb, L.S., Goldman, F. & Di Stasi, A. Improving the safety of cell therapy products by suicide gene transfer. Front. Pharmacol. 5, 254 (2014).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank members of our laboratory for contributions in this area. Supported by the National Health and Medical Research Council of Australia (1078671, 1098960 and 1093566 to M.J.S.; 1107417 to C.G.; 1027472, 1049407, 1066770 and 1057852 to N.D.H.; and an Independent Research Institute Infrastructure Support Scheme grant to N.D.H.), the Cancer Research Institute (CLIP grant to M.J.S.), the Cancer Council of Queensland (1083776 to M.J.S.), the Victorian State Government (Operational Infrastructure Scheme grant to N.D.H.) and the Harry J Lloyd Charitable Trust (N.D.H.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mark J Smyth.

Ethics declarations

Competing interests

M.J.S. has research agreements with Medimmune and Bristol Myers Squibb.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guillerey, C., Huntington, N. & Smyth, M. Targeting natural killer cells in cancer immunotherapy. Nat Immunol 17, 1025–1036 (2016). https://doi.org/10.1038/ni.3518

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.3518

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer