Natural Killer Cell Dysfunction In Human Bladder Cancer Is Caused By Tissue-Specific Suppression of SLAMF6 Signaling

NK cells are innate lymphocytes critical for surveillance of viruses and tumors, however the mechanisms underlying NK cell dysfunction in cancer are incompletely understood. We assessed the effector function of NK cells from bladder cancer patients and found severe dysfunction in NK cells derived from tumors versus peripheral blood. While both peripheral and tumor-infiltrating NK cells exhibited conserved patterns of inhibitory receptor over-expression, this did not explain the observed defects in NK surveillance in bladder tumors. Rather, TME-specific TGF-β and metabolic perturbations such as hypoxia directly suppressed NK cell function. Specifically, an oxygen-dependent reduction in signaling through SLAMF6 was mechanistically responsible for poor NK cell function, as tumor-infiltrating NK cells cultured ex vivo under normoxic conditions exhibited complete restoration of function, while deletion of SLAMF6 abrogated NK cell cytolytic function even under normoxic conditions. Collectively, this work highlights the role of tissue-specific factors in dictating NK cell function, and implicates SLAMF6 signaling as a rational target for immuno-modulation to improve NK cell function in bladder cancer. ![Graphical Abstract][1] Graphical Abstract ### Competing Interest Statement N.B. is an advisor, consultant, or board member for Apricity, Carisma Therapeutics, CureVac, Genotwin, Novartis, Primevax, Rome Therapeutics, Tempest Therapeutics, and ATP, and has received research support from Dragonfly Therapeutics, Harbour Biomed, and Regeneron. A.H. receives research funding from Astra Zeneca and has served on advisory boards for Purple Biotech and UroGen. M.D.G. receives research funding from Bristol Myers Squibb, Novartis, Dendreon, Astra Zeneca, Merck, and Genentech, and has served as an advisory board member/consultant for Bristol Myers Squibb, Merck, Genentech, AstraZeneca, Pfizer, EMD Serono, SeaGen, Janssen, Numab, Dragonfly, GlaxoSmithKline, Basilea, UroGen, Rappta Therapeutics, Alligator, Silverback, Fujifilm, Curis, Gilead, Bicycle, Asieris, Abbvie, Analog Devices, Veracyte, Daiichi, and Aktis. A.M.F., M.A.T., D.Y., J.H.N., S.B., E.G.G., K.S., A.A. A.P., F.A, H.A., J.T., and J.P.S. declare no competing interests. [1]: pending:yes