NK cell effector functions are differentially regulated by hypoxic conditions (TUM9P.1014)

Abstract

Abstract NK cells provide the first line of defense against tumor and viruses, without the requirement for prolonged pre-activation. However, anti-tumor function of NK cells is progressively dampened in the terminal stages of cancer patients, largely associated with the tumor-induced immune evasion mechanism. Hypoxic tumor environment provides once such mechanism providing NK cell tolerance, and become a potential therapeutic problem to overcome in the patients of solid cancer for NK immunotherapy. To better understand the effect of hypoxia on NK cells, we assessed the anti-tumor function of NK cells in response to decreasing concentration of O2 concentration. As expected, NK cells cultured in severe hypoxia, 0.5% O2, demonstrated diminished cytotoxicity and IFNg against A375 melanoma targets and failed to expand to a larger number ex vivo. However, to our surprise, NK cells cultured in mild hypoxia, 1.5% O2, were expanded to a much higher level and mounted increased anti-tumor effector function, both in normoxic and hypoxic conditions. NK cells grown in mild hypoxia demonstrate upregulation of major activating NK cell receptors, NCRs, while inhibiting apoptosis during ex-vivo expansion. Thus, NK cells respond differentially to O2 concentration, and mild hypoxic conditions can indeed facilitate the expansion and function of NK cells that can overcome NK cell intolerance in the patients undergoing NK cell immunotherapy.