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

Jens H.W Pahl,Erich Rajkovic,Adelheid Cerwenka,Uwe Reusch,Joachim Koch,Thorsten Gantke,Jana-Julia Götz,Martin Treder,Annette Arnold

doi:10.1158/2326-6066.cir-17-0550

Abstract

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.

Highlights

Natural killer (NK) cells are cytotoxic innate lymphoid cells that are in the first line of defense against virally infected cells and cancer cells [1]
Lysis of CD19þ/CD30– Daudi cells could be increased by AFM12, a tetravalent bispecific CD19/CD16A antibody used as a control (Fig. 1A)
We demonstrate that CD16A activation by tetravalent, bispecific AFM13 improved the functionality of NK cells beyond their classical antibody-dependent cytotoxicity and IFNg production elicited in response to CD30þ lymphoma cells, which are otherwise poorly killed by NK cells

Summary

Introduction

Natural killer (NK) cells are cytotoxic innate lymphoid cells that are in the first line of defense against virally infected cells and cancer cells [1]. In contrast to CD8þ T cells, NK cells recognize abnormal cells through a defined set of germlineencoded receptors, such as the inhibitory KIR and NKG2A receptors and the activating NKG2D, DNAM-1, and NKp30 receptors [2, 3]. NK cells respond to cells that display an incompatible repertoire or reduced levels of MHC class I molecules, enabling recognition of certain cancer cells which may evade CD8þ T cell responses. Low expression of inhibitory ligands in combination with high levels of activating ligands on target cells result in NK cell activation and the release of perforin and granzyme B, mediating target cell death [4]. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

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