Human effector memory T lymphocytes express pre-existing hypoxia-adaptation genes and are resistant to hypoxia (P2036)

Abstract

Abstract Hypoxia that is a hallmark of solid tumors is considered an inhibitory mechanism that hampers the clinical benefits of T-cell-based immunotherapy in cancer patients. Studies have shown indeed that circulating human peripheral blood (PB) T cells activated in hypoxia have reduced proliferation and survival. However, antigen-specific T cells generated ex vivo and adoptively transferred in cancer patients are mostly (>80%) effector memory T cells (TEM) while this subset represents <20% of total circulating PB T cells. How hypoxia selectively influences TEM cells has not been studied. In sharp contrast with T cells from PB, we found that proliferation, survival and cytotoxic functions of ex vivo expanded T cells are augmented in hypoxia. Importantly, we found that TEM cells directly isolated from PB show properties similar to those of expanded T cells when compared to isolated naïve and central memory cells, suggesting that the resistance to hypoxia is an intrinsic property of TEM. Finally, resistance to hypoxia is associated with an increased hypoxia-adaptation genes. Expression of HIF-1a and downstream glycolytic genes are indeed higher in TEM cells, suggesting a genetic “pre-adaptation status” of TEM to hypoxia. Together, we show that primary TEM and ex vivo generated antigen-specific T cells are resistant to hypoxia, and this finding has relevant implication for the clinical translation of adoptive immunotherapy in cancer patients.