细胞毒性T细胞
细胞毒性
生物
肿瘤微环境
细胞生物学
柠檬酸循环
生物化学
CD8型
新陈代谢
免疫系统
癌症研究
体外
免疫学
作者
Ilaria Elia,Jared H. Rowe,Sheila Johnson,Shakchhi Joshi,Giulia Notarangelo,Kiran Kurmi,Sarah A. Weiss,Gordon J. Freeman,Arlene H. Sharpe,Marcia C. Haigis
出处
期刊:Cell Metabolism
[Elsevier]
日期:2022-08-01
卷期号:34 (8): 1137-1150.e6
被引量:82
标识
DOI:10.1016/j.cmet.2022.06.008
摘要
The tumor microenvironment (TME) is a unique metabolic niche that can inhibit T cell metabolism and cytotoxicity. To dissect the metabolic interplay between tumors and T cells, we establish an in vitro system that recapitulates the metabolic niche of the TME and allows us to define cell-specific metabolism. We identify tumor-derived lactate as an inhibitor of CD8+ T cell cytotoxicity, revealing an unexpected metabolic shunt in the TCA cycle. Metabolically fit cytotoxic T cells shunt succinate out of the TCA cycle to promote autocrine signaling via the succinate receptor (SUCNR1). Cytotoxic T cells are reliant on pyruvate carboxylase (PC) to replenish TCA cycle intermediates. By contrast, lactate reduces PC-mediated anaplerosis. The inhibition of pyruvate dehydrogenase (PDH) is sufficient to restore PC activity, succinate secretion, and the activation of SUCNR1. These studies identify PDH as a potential drug target to allow CD8+ T cells to retain cytotoxicity and overcome a lactate-enriched TME.
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