TY  - JOUR
AU  - Pahl, Jens
AU  - Koch, Joachim
AU  - Götz, Jana
AU  - Arnold, Annette
AU  - Reusch, Uwe
AU  - Gantke, Thorsten
AU  - Rajkovic, Erich
AU  - Treder, Martin
AU  - Cerwenka, Adelheid
TI  - CD16A Activation of NK Cells Promotes NK Cell Proliferation and Memory-Like Cytotoxicity against Cancer Cells.
JO  - Cancer immunology research
VL  - 6
IS  - 5
SN  - 2326-6074
CY  - Philadelphia, Pa.
PB  - AACR
M1  - DKFZ-2018-00581
SP  - 517 - 527
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:29514797
DO  - DOI:10.1158/2326-6066.CIR-17-0550
UR  - https://inrepo02.dkfz.de/record/132942
ER  -