当前位置: X-MOL 学术Cell Metab. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8+ T cells
Cell Metabolism ( IF 29.0 ) Pub Date : 2022-07-11 , DOI: 10.1016/j.cmet.2022.06.008
Ilaria Elia 1 , Jared H Rowe 2 , Sheila Johnson 3 , Shakchhi Joshi 3 , Giulia Notarangelo 3 , Kiran Kurmi 3 , Sarah Weiss 4 , Gordon J Freeman 5 , Arlene H Sharpe 4 , Marcia C Haigis 3
Affiliation  

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.



中文翻译:

肿瘤细胞通过改变 CD8+ T 细胞中的丙酮酸利用和琥珀酸信号传导来控制抗肿瘤免疫反应

肿瘤微环境(TME)是一个独特的代谢生态位,可以抑制T细胞代谢和细胞毒性。为了剖析肿瘤和 T 细胞之间的代谢相互作用,我们建立了一个体外系统,该系统概括了 TME 的代谢生态位,并使我们能够定义细胞特异性代谢。我们确定肿瘤来源的乳酸是 CD8 + T 细胞细胞毒性的抑制剂,揭示了 TCA 循环中意想不到的代谢分流。代谢适合的细胞毒性 T 细胞将琥珀酸从 TCA 循环中分流出来,以通过琥珀酸受体 (SUCNR1) 促进自分泌信号传导。细胞毒性 T 细胞依赖丙酮酸羧化酶 (PC) 来补充 TCA 循环中间体。相比之下,乳酸可减少 PC 介导的回补。丙酮酸脱氢酶 (PDH) 的抑制足以恢复 PC 活性、琥珀酸分泌和 SUCNR1 的激活。这些研究将 PDH 确定为潜在的药物靶点,使 CD8 + T 细胞保留细胞毒性并克服富含乳酸的 TME。

更新日期:2022-07-11
down
wechat
bug