HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells.

Hypoxia is a common feature in various pathophysiological contexts, including tumor microenvironment, and IFN-γ is instrumental for anti-tumor immunity. HIF1α has long been known as a primary regulator of cellular adaptive responses to hypoxia, but its role in IFN-γ induction in hypoxic T cells is unknown. Here, we show that the HIF1α-glycolysis axis controls IFN-γ induction in both human and mouse T cells, activated under hypoxia. Specific deletion of HIF1α in T cells (Hif1α^–/–) and glycolytic inhibition suppresses IFN-γ induction. Conversely, HIF1α stabilization by hypoxia and VHL deletion in T cells (Vhl^–/–) increases IFN-γ production. Hypoxic Hif1α^–/– T cells are less able to kill tumor cells in vitro, and tumor-bearing Hif1α^–/– mice are not responsive to immune checkpoint blockade (ICB) therapy in vivo. Mechanistically, loss of HIF1α greatly diminishes glycolytic activity in hypoxic T cells, resulting in depleted intracellular acetyl-CoA and attenuated activation-induced cell death (AICD). Restoration of intracellular acetyl-CoA by acetate supplementation re-engages AICD, rescuing IFN-γ production in hypoxic Hif1α^–/– T cells and re-sensitizing Hif1α^–/– tumor-bearing mice to ICB. In summary, we identify HIF1α-regulated glycolysis as a key metabolic control of IFN-γ production in hypoxic T cells and ICB response. Anti-cancer immunity relies on the effector functions (e.g., IFNγ production) of T cells that reside in a hypoxic tumor microenvironment. Here, the authors show that HIF1α-controlled glycolysis is an important driver of IFNγ production in hypoxic T cells, governing anti-tumor immunity. [ABSTRACT FROM AUTHOR]