生物
糖酵解
肿瘤微环境
癌症研究
癌症
PI3K/AKT/mTOR通路
T细胞
肿瘤进展
封锁
抗原
癌细胞
葡萄糖摄取
免疫系统
细胞生物学
受体
免疫学
酶
生物化学
肿瘤细胞
内分泌学
信号转导
胰岛素
遗传学
作者
Chih‐Hao Chang,Jing Qiu,David O’Sullivan,Michael D. Buck,Takuro Noguchi,Jonathan D. Curtis,Qiongyu Chen,Mariel Gindin,Matthew M. Gubin,Gerritje J. W. van der Windt,Elena Tonc,Robert D. Schreiber,Edward J. Pearce,Erika L. Pearce
出处
期刊:Cell
[Elsevier]
日期:2015-09-01
卷期号:162 (6): 1229-1241
被引量:2163
标识
DOI:10.1016/j.cell.2015.08.016
摘要
Failure of T cells to protect against cancer is thought to result from lack of antigen recognition, chronic activation, and/or suppression by other cells. Using a mouse sarcoma model, we show that glucose consumption by tumors metabolically restricts T cells, leading to their dampened mTOR activity, glycolytic capacity, and IFN-γ production, thereby allowing tumor progression. We show that enhancing glycolysis in an antigenic “regressor” tumor is sufficient to override the protective ability of T cells to control tumor growth. We also show that checkpoint blockade antibodies against CTLA-4, PD-1, and PD-L1, which are used clinically, restore glucose in tumor microenvironment, permitting T cell glycolysis and IFN-γ production. Furthermore, we found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of glycolysis enzymes, reflecting a role for PD-L1 in tumor glucose utilization. Our results establish that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer.
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