CD16A Activation of NK Cells Promotes NK Cell Proliferation and Memory-Like Cytotoxicity against Cancer Cells

Cancer Immunol Res. 2018 May;6(5):517-527. doi: 10.1158/2326-6066.CIR-17-0550. Epub 2018 Mar 7.


CD16A is a potent cytotoxicity receptor on human natural killer (NK) cells, which can be exploited by therapeutic bispecific antibodies. So far, the effects of CD16A-mediated activation on NK cell effector functions beyond classical antibody-dependent cytotoxicity have remained poorly elucidated. Here, we investigated NK cell responses after exposure to therapeutic antibodies such as the tetravalent bispecific antibody AFM13 (CD30/CD16A), designed for the treatment of Hodgkin lymphoma and other CD30+ lymphomas. Our results reveal that CD16A engagement enhanced subsequent IL2- and IL15-driven NK cell proliferation and expansion. This effect involved the upregulation of CD25 (IL2Rα) and CD132 (γc) on NK cells, resulting in increased sensitivity to low-dose IL2 or to IL15. CD16A engagement initially induced NK cell cytotoxicity. The lower NK cell reactivity observed 1 day after CD16A engagement could be recovered by reculture in IL2 or IL15. After reculture in IL2 or IL15, these CD16A-experienced NK cells exerted more vigorous IFNγ production upon restimulation with tumor cells or cytokines. Importantly, after reculture, CD16A-experienced NK cells also exerted increased cytotoxicity toward different tumor targets, mainly through the activating NK cell receptor NKG2D. Our findings uncover a role for CD16A engagement in priming NK cell responses to restimulation by cytokines and tumor cells, indicative of a memory-like functionality. Our study suggests that combination of AFM13 with IL2 or IL15 may boost NK cell antitumor activity in patients by expanding tumor-reactive NK cells and enhancing NK cell reactivity, even upon repeated tumor encounters. Cancer Immunol Res; 6(5); 517-27. ©2018 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antibodies, Bispecific / pharmacology
  • Cell Proliferation* / drug effects
  • Cells, Cultured
  • Cytotoxicity, Immunologic / drug effects
  • Cytotoxicity, Immunologic / physiology*
  • Humans
  • Immunologic Memory / drug effects
  • Immunologic Memory / physiology*
  • Immunotherapy / methods
  • Jurkat Cells
  • K562 Cells
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / physiology*
  • Mice
  • Neoplasms / immunology*
  • Neoplasms / therapy
  • Receptors, IgG / immunology*
  • Receptors, IgG / metabolism


  • Antibodies, Bispecific
  • FCGR3A protein, human
  • Receptors, IgG