Enhancing IL-15-driven natural killer cell proliferation by targeting the regulatory checkpoint ADAM17 to improve tumor cell killing

Abstract

Natural killer (NK) cells are cytotoxic innate lymphoid cells. Unlike T and B cells, NK cells do not express an antigen-specific receptor and instead use germline-encoded activating and inhibitory receptors to interrogate cells they encounter. Their activating receptors lead to quick activation and destruction of targeted cells, including tumor cells. In addition to cytolytic factors, activated NK cells release various cytokines and chemokines that can broadly modulate the immune response. Due to these effector functions, NK cells are being widely evaluated as a cancer immunotherapy. Whether endogenous cells and or autologous or allogeneic adoptive cell therapies, NK cells require cytokine treatment to drive their proliferation, prolong their survival, and increase their function. IL-15 stimulation is a standard approach. Cytokines, including IL-15, however, activate ADAM17 (a disintegrin and metalloproteinase-17) in NK cells. ADAM17 is a membrane protease that cleaves various activating receptors and adhesion molecules as a negative feedback process to control NK cell responses. ADAM17 induction likely diminishes the anti-tumor potential of NK cell therapies. Medi-1 is a human IgG1 mAb that blocks ADAM17 function and it markedly enhanced NK cell activation and proliferation by IL-15 in vitro and in vivo. My research focused on the mechanisms underlying these events. These studies demonstrate that the synergistic effects of Medi-1 treatment on IL-15 stimulation required its Fc region. CD16A is the main activating IgG Fc receptor on NK cells and a well-described ADAM17 substrate. My studies addressed the hypothesis that Medi-1, when bound to ADAM17 on NK cells, blocks the shedding of CD16A and is also engaged by CD16A, inducing and extending its stimulation of NK cells. Medi-1 treatment did not cause apparent NK cell fratricide or dysfunction. CD25 and CD137 were distinctly upregulated by NK cells treated with Medi-1 and IL-15. Moreover, CD137 upregulation occurred selectively by NK cells expressing CD16A. Blocking CD137 by different approaches diminished IL-15-driven NK cell proliferation. These findings show for the first time that IL-15-driven NK cell proliferation in the presence of other mononuclear cells involved CD137, as did their augmented proliferation mediated by Medi-1 treatment. Due to these multifaceted effects, Medi-1 represents a potential novel strategy to enhance IL-15-driven persistence and function of NK cell immunotherapies in cancer patients.