PDF(Pubmed)
Abstract：
The role of HIF1α-glycolysis in regulating IFN-γ induction in hypoxic T cells is unknown. Given that hypoxia is a common feature in a wide array of pathophysiological contexts such as tumor and that IFN-γ is instrumental for protective immunity, it is of great significance to gain a clear idea on this. Combining pharmacological and genetic gain-of-function and loss-of-function approaches, we find that HIF1α-glycolysis 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 significantly abrogate IFN-γ induction. Conversely, HIF1α stabilization in T cells by hypoxia and VHL deletion (VHL-/-) promotes IFN-γ production. Mechanistically, reduced IFN-γ production in hypoxic HIF1α-/- T cells is due to attenuated activation-induced cell death but not proliferative defect. We further show that depletion of intracellular acetyl-CoA is a key metabolic underlying mechanism. Hypoxic HIF1α-/- T cells are less able to kill tumor cells, and HIF1α-/- tumor-bearing mice are not responsive to immune checkpoint blockade (ICB) therapy, indicating loss of HIF1α in T cells is a major mechanism of therapeutic resistance to ICBs. Importantly, acetate supplementation restores IFN-γ production in hypoxic HIF1α-/- T cells and re-sensitizes HIF1α-/- tumor-bearing mice to ICBs, providing an effective strategy to overcome ICB resistance. Taken together, our results highlight T cell HIF1α-anaerobic glycolysis as a principal mediator of IFN-γ induction and anti-tumor immunity. Considering that acetate supplementation (i.e., glycerol triacetate (GTA)) is approved to treat infants with Canavan disease, we envision a rapid translation of our findings, justifying further testing of GTA as a repurposed medicine for ICB resistance, a pressing unmet medical need.
摘要：
HIF1α-糖酵解在调节低氧T细胞中的IFN-γ诱导中的作用是未知的。鉴于缺氧是广泛的病理生理背景（如肿瘤）中的共同特征，并且IFN-γ有助于保护性免疫，对此有一个清晰的想法具有重要意义。结合药理学和遗传功能获得和功能丧失的方法，我们发现HIF1α-糖酵解控制缺氧激活的人和小鼠T细胞中IFN-γ的诱导。T细胞中HIF1α的特异性缺失(HIF1α-/-)和糖酵解抑制显著消除IFN-γ诱导。相反，通过缺氧和VHL缺失(VHL-/-)在T细胞中稳定HIF1α促进IFN-γ产生。机械上,低氧HIF1α-/-T细胞中IFN-γ产生的减少是由于减弱的活化诱导的细胞死亡而不是增殖缺陷。我们进一步表明，细胞内乙酰辅酶A的消耗是一个关键的代谢机制。缺氧HIF1α-/-T细胞对肿瘤细胞的杀伤能力较差，和HIF1α-/-荷瘤小鼠对免疫检查点阻断（ICB）治疗无反应，表明T细胞中HIF1α的丢失是ICB治疗抗性的主要机制。重要的是,补充乙酸盐可恢复低氧HIF1α-/-T细胞中IFN-γ的产生，并使HIF1α-/-荷瘤小鼠对ICB重新敏感，提供了克服ICB耐药性的有效策略。一起来看,我们的结果强调T细胞HIF1α-厌氧糖酵解是IFN-γ诱导和抗肿瘤免疫的主要介质。考虑到乙酸盐的补充(即，甘油三乙酸酯（GTA）被批准用于治疗患有Canavan病的婴儿，我们设想快速转化我们的发现，证明GTA作为ICB耐药性再利用药物的进一步测试，迫切的未满足的医疗需求。
