HIF-1α Is a Metabolic Switch between Glycolytic-Driven Migration and Oxidative Phosphorylation-Driven Immunosuppression of Tregs in Glioblastoma
HIF-1α Is a Metabolic Switch between Glycolytic-Driven Migration and Oxidative Phosphorylation-Driven Immunosuppression of Tregs in Glioblastoma
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DOI：
10.1016/j.celrep.2019.03.029
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发表时间：
2019-04-02
期刊：
影响因子：
8.8
通讯作者：
Lesniak, Maciej S.
中科院分区：
文献类型：
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作者：
Miska, Jason;Lee-Chang, Catalina;Lesniak, Maciej S.
调节性T细胞（Tcells）迁移到缺氧肿瘤微环境并在其中发挥作用的机制尚不清楚。我们的研究表明，在缺氧条件下，特异性消除TclO中的缺氧诱导因子1 α（HIF-1 α）导致与野生型TclO相比增强的CD 8（+）T细胞抑制，这是由于丙酮酸盐进入线粒体的增加。重要的是，HIF-1 α缺陷型Treg受到脂质氧化抑制的影响最小，脂质氧化是肿瘤Treg代谢的关键燃料。在缺氧条件下，HIF-1 α引导葡萄糖远离线粒体，使TGF 1 α依赖于脂肪酸进行缺氧肿瘤内的线粒体代谢。事实上，抑制脂质氧化可以提高胶质瘤小鼠的存活率。有趣的是，HIF-1 α缺陷型Treg小鼠在胶质瘤鼠模型中表现出显著增强的动物存活率，这是由于它们的迁移能力受阻，这解释了它们在荷瘤小鼠中的丰度降低。因此，HIF-1 α在糖酵解驱动的迁移和氧化磷酸化驱动的免疫抑制之间充当TcB的代谢开关。
The mechanisms by which regulatory T cells (Tregs) migrate to and function within the hypoxic tumor microenvironment are unclear. Our studies indicate that specific ablation of hypoxia-inducible factor 1 alpha (HIF-1 alpha) in Tregs results in enhanced CD8(+) T cell suppression versus wild-type Tregs under hypoxia, due to increased pyruvate import into the mitochondria. Importantly, HIF-1 alpha-deficient Tregs are minimally affected by the inhibition of lipid oxidation, a fuel that is critical for Treg metabolism in tumors. Under hypoxia, HIF-1 alpha directs glucose away from mitochondria, leaving Tregs dependent on fatty acids for mitochondrial metabolism within the hypoxic tumor. Indeed, inhibition of lipid oxidation enhances the survival of mice with glioma. Interestingly, HIF-1 alpha-deficient-Treg mice exhibit significantly enhanced animal survival in a murine model of glioma, due to their stymied migratory capacity, explaining their reduced abundance in tumor-bearing mice. Thus HIF-1 alpha acts as a metabolic switch for Tregs between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression.