Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, 676 North St. Clair Street, Suite 2210, Chicago, IL 60611, USA.
Department of Medicine, Feinberg School of Medicine, Northwestern University, 676 North St. Clair Street, Suite 2330, Chicago, IL 60611, USA.
Cell Rep. 2019 Apr 2;27(1):226-237.e4. doi: 10.1016/j.celrep.2019.03.029.
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 1α (HIF-1α) 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-1α-deficient Tregs are minimally affected by the inhibition of lipid oxidation, a fuel that is critical for Treg metabolism in tumors. Under hypoxia, HIF-1α 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-1α-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-1α acts as a metabolic switch for Tregs between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression.
调节性 T 细胞（Tregs）向缺氧肿瘤微环境迁移并在其中发挥功能的机制尚不清楚。我们的研究表明，在缺氧条件下，Tregs 中特定的缺氧诱导因子 1α（HIF-1α）缺失会导致 CD8 T 细胞抑制作用增强，与野生型 Tregs 相比，这是由于丙酮酸向线粒体的导入增加所致。重要的是，HIF-1α 缺陷型 Tregs 受脂质氧化抑制的影响最小，而脂质氧化是肿瘤中 Treg 代谢的关键燃料。在缺氧条件下，HIF-1α 将葡萄糖从线粒体中转移出去，使 Tregs 依赖于脂肪酸进行缺氧肿瘤内的线粒体代谢。事实上，抑制脂质氧化可增强患有神经胶质瘤小鼠的存活率。有趣的是，由于 HIF-1α 缺陷型 Tregs 的迁移能力受到阻碍，它们在神经胶质瘤的小鼠模型中表现出明显增强的动物存活率，这解释了它们在荷瘤小鼠中丰度降低的原因。因此，HIF-1α 作为 Tregs 代谢的开关，在糖酵解驱动的迁移和氧化磷酸化驱动的免疫抑制之间发挥作用。
