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

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 (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. .

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…Inhibition of CD16 shedding through ADAM17 blockade may increase NK cell activation in the TME, thereby potentiating antibody treatments targeting NK cells (251,255,256). Sustaining this CD16 mediated activity may be especially important, as the Cerwenka group showed that NK cell engagement through CD16 might prime NK cells against cancers by providing them with memory-like effects (257).…”

Targeting Natural Killer Cells for Tumor Immunotherapy

“…A bi-specific Ab-recognizing CS1-NKG2D, which comprises an anti-NKG2D scFv and an anti-CS1 scFv, showed enhanced cytotoxicity and cytokine production from NK cells and significantly prolonged their survival in a multiple myeloma xenograft NOD-SCID IL2γc−/− (NSG) mouse model (104). A novel CD30/CD16A tetravalent bispecific Ab (AFM13), which has a longer half-life compared with that of other bi-/trispecific Abs, is currently under evaluation in a phase II clinical trial to treat patients with relapsed/refractory Hodgkin's lymphomas (NCT03192202) (105,106).…”

From the “missing self” hypothesis to adaptive NK cells: Insights of NK cell-mediated effector functions in immune surveillance

“…Importantly, most of these phenotypic changes were due to epigenetic modifications, providing a mechanism for altered signaling and function in adaptive NK cells compared to conventional NK cells. Although the signals and the molecular mechanisms responsible for the expansion of adaptive NK cells remain unknown, recent data suggest a critical role for CD16 . Under this scenario, CD16 engagement by anti‐HCMV antibodies may promote the differentiation and further maintenance of adaptive NK cells.…”

“…Although the signals and the molecular mechanisms responsible for the expansion of adaptive NK cells remain unknown, recent data suggest a critical role for CD16. 163 Under this scenario, CD16 engagement by anti-HCMV antibodies may promote the differentiation and further maintenance of adaptive NK cells. Whether adaptive NK cells emerge in other scenarios where specific antibodies are chronically elevated either in health or disease remains to be determined.…”