Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham (UAB-SOM), Birmingham, AL, USA.
Genomics Core Laboratory, Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, Alaska, USA.
Nat Commun. 2024 Oct 30;15(1):9394. doi: 10.1038/s41467-024-53593-8.
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.
缺氧是各种病理生理情况下的共同特征，包括肿瘤微环境，IFN-γ 是抗肿瘤免疫的关键。HIF1α 长期以来一直被认为是细胞对缺氧适应性反应的主要调节因子，但它在缺氧 T 细胞中 IFN-γ 诱导中的作用尚不清楚。在这里，我们表明 HIF1α-糖酵解轴控制人类和小鼠 T 细胞在缺氧条件下的 IFN-γ 诱导。T 细胞中 HIF1α 的特异性缺失（Hif1α）和糖酵解抑制抑制 IFN-γ 的诱导。相反，通过缺氧和 T 细胞中 VHL 的缺失稳定 HIF1α（Vhl）会增加 IFN-γ 的产生。缺氧的 Hif1α T 细胞在体外杀死肿瘤细胞的能力较弱，并且荷瘤 Hif1α 小鼠对体内免疫检查点阻断（ICB）治疗无反应。在机制上，HIF1α 的缺失大大降低了缺氧 T 细胞中的糖酵解活性，导致细胞内乙酰辅酶 A 耗尽和激活诱导的细胞死亡（AICD）减弱。通过补充醋酸盐来恢复细胞内乙酰辅酶 A 会重新激活 AICD，从而挽救缺氧 Hif1α T 细胞中的 IFN-γ 产生，并使 Hif1α 荷瘤小鼠重新对 ICB 敏感。总之，我们确定 HIF1α 调节的糖酵解是缺氧 T 细胞中 IFN-γ 产生和 ICB 反应的关键代谢控制因素。
