为了剖析肿瘤和T细胞之间的代谢相互作用，研究人员建立了一个体外系统，再现了肿瘤微环境（TME）的代谢微环境，并能够定义细胞的特定代谢。研究人员确定肿瘤衍生的乳酸是CD8+T细胞细胞毒性的抑制剂，并揭示了TCA循环中一个意想不到的代谢分流。代谢适应的细胞毒性T细胞将琥珀酸分流出TCA循环，通过琥珀酸受体（SUCNR1）促进自分泌信号。细胞毒性T细胞依赖丙酮酸羧化酶（PC）来补充TCA循环的中间产物。
相比之下，乳酸会减少PC介导的回补。抑制丙酮酸脱氢酶（PDH）足以恢复PC的活性、琥珀酸的分泌和SUCNR1的激活。这些研究确定PDH是一个潜在的药物靶点，使CD8+T细胞保持细胞毒性并克服富含乳酸的TME。
据悉，肿瘤微环境（TME）是一个独特的代谢微环境，可以抑制T细胞的代谢和细胞毒性。
附：英文原文
Title: Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8+ T cells
Author: Ilaria Elia, Jared H. Rowe, Sheila Johnson, Shakchhi Joshi, Giulia Notarangelo, Kiran Kurmi, Sarah Weiss, Gordon J. Freeman, Arlene H. Sharpe, Marcia C. Haigis
Issue&Volume: 2022-07-11
Abstract: The tumor microenvironment (TME) is a unique metabolic niche that can inhibit T cellmetabolism and cytotoxicity. To dissect the metabolic interplay between tumors andT cells, we establish an in vitro system that recapitulates the metabolic niche of the TME and allows us to definecell-specific metabolism. We identify tumor-derived lactate as an inhibitor of CD8+ T cell cytotoxicity, revealing an unexpected metabolic shunt in the TCA cycle. Metabolicallyfit cytotoxic T cells shunt succinate out of the TCA cycle to promote autocrine signalingvia the succinate receptor (SUCNR1). Cytotoxic T cells are reliant on pyruvate carboxylase(PC) to replenish TCA cycle intermediates. By contrast, lactate reduces PC-mediatedanaplerosis. The inhibition of pyruvate dehydrogenase (PDH) is sufficient to restorePC activity, succinate secretion, and the activation of SUCNR1. These studies identifyPDH as a potential drug target to allow CD8+ T cells to retain cytotoxicity and overcome a lactate-enriched TME.
DOI: 10.1016/j.cmet.2022.06.008
Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00228-5
Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
官方网址：https://www.cell.com/cell-metabolism/home
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本期文章：《细胞—代谢》：Online/在线发表
