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

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. He...

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Bibliographic Details
Published in:	Cancer immunology research 2018-05, Vol.6 (5), p.517-527
Main Authors:	Pahl, Jens H W, Koch, Joachim, Götz, Jana-Julia, Arnold, Annette, Reusch, Uwe, Gantke, Thorsten, Rajkovic, Erich, Treder, Martin, Cerwenka, Adelheid
Format:	Article
Language:	eng
Subjects:	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
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Summary:	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 (γ ) 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. .
ISSN:	2326-6066 2326-6074