| First Author | Shen H | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 9394 |
| PubMed ID | 39477954 | Mgi Jnum | J:360895 |
| Mgi Id | MGI:7765597 | Doi | 10.1038/s41467-024-53593-8 |
| Citation | Shen H, et al. (2024) HIF1alpha-regulated glycolysis promotes activation-induced cell death and IFN-gamma induction in hypoxic T cells. Nat Commun 15(1):9394 |
| abstractText | Hypoxia is a common feature in various pathophysiological contexts, including tumor microenvironment, and IFN-gamma is instrumental for anti-tumor immunity. HIF1alpha has long been known as a primary regulator of cellular adaptive responses to hypoxia, but its role in IFN-gamma induction in hypoxic T cells is unknown. Here, we show that the HIF1alpha-glycolysis axis controls IFN-gamma induction in both human and mouse T cells, activated under hypoxia. Specific deletion of HIF1alpha in T cells (Hif1alpha(-/-)) and glycolytic inhibition suppresses IFN-gamma induction. Conversely, HIF1alpha stabilization by hypoxia and VHL deletion in T cells (Vhl(-/-)) increases IFN-gamma production. Hypoxic Hif1alpha(-/-) T cells are less able to kill tumor cells in vitro, and tumor-bearing Hif1alpha(-/-) mice are not responsive to immune checkpoint blockade (ICB) therapy in vivo. Mechanistically, loss of HIF1alpha 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-gamma production in hypoxic Hif1alpha(-/-) T cells and re-sensitizing Hif1alpha(-/-) tumor-bearing mice to ICB. In summary, we identify HIF1alpha-regulated glycolysis as a key metabolic control of IFN-gamma production in hypoxic T cells and ICB response. |
