氧化磷酸化
糖酵解
肿瘤微环境
免疫抑制
缺氧(环境)
癌症研究
线粒体
细胞生物学
CD8型
生物
β氧化
脂质代谢
免疫系统
新陈代谢
化学
免疫学
生物化学
氧气
有机化学
作者
Jason Miska,Catalina Lee-Chang,Aida Rashidi,Megan E. Muroski,Alan L. Chang,Aurora Lopez-Rosas,Peng Zhang,Wojciech K. Panek,Àlex Cordero,Yu Han,Atique U. Ahmed,Navdeep S. Chandel,Maciej S. Lesniak
出处
期刊:Cell Reports
[Elsevier]
日期:2019-04-01
卷期号:27 (1): 226-237.e4
被引量:191
标识
DOI:10.1016/j.celrep.2019.03.029
摘要
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.
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