瑞士洛桑联邦理工学院Li Tang、洛桑大学Ping-Chih Ho等研究人员合作发现，IL-10对终末耗竭CD8⁺T细胞的代谢重编程可增强抗肿瘤免疫力。该项研究成果于2021年5月24日在线发表在《自然—免疫学》杂志上。

研究人员发现，半衰期延长的白细胞介素10-Fc融合蛋白通过促进氧化磷酸化直接并有效地增强了终末耗竭CD8⁺肿瘤浸润淋巴细胞的扩增和效应子功能，该过程不依赖于祖细胞耗竭的T细胞。白细胞介素10–Fc是一种安全高效的代谢干预措施，与过继T细胞转移免疫疗法协同作用，可消除大多数治疗后小鼠中形成的实体瘤并持久治愈。这些发现表明，通过上调线粒体丙酮酸载体依赖的氧化磷酸化来进行代谢重编程可以使终末耗竭的T细胞恢复活力，并增强对癌症免疫疗法的反应。

据了解，T细胞耗竭是癌症免疫疗法的主要障碍之一。在精疲力竭的CD8⁺肿瘤浸润淋巴细胞中，终末耗竭的亚群由于其细胞毒性效应功能而直接杀死肿瘤细胞。但是，该亚群对免疫检查点封锁无反应，并且难以通过增殖能力恢复来重新激活。

附：英文原文

Title: Metabolic reprogramming of terminally exhausted CD8 + T cells by IL-10 enhances anti-tumor immunity

Author: Yugang Guo, Yu-Qing Xie, Min Gao, Yang Zhao, Fabien Franco, Mathias Wenes, Imran Siddiqui, Alessio Bevilacqua, Haiping Wang, Hanshuo Yang, Bing Feng, Xin Xie, Catherine M. Sabatel, Benjamin Tschumi, Amphun Chaiboonchoe, Yuxi Wang, Weimin Li, Weihua Xiao, Werner Held, Pedro Romero, Ping-Chih Ho, Li Tang

Issue&Volume: 2021-05-24

Abstract: T cell exhaustion presents one of the major hurdles to cancer immunotherapy. Among exhausted CD8+ tumor-infiltrating lymphocytes, the terminally exhausted subset contributes directly to tumor cell killing owing to its cytotoxic effector function. However, this subset does not respond to immune checkpoint blockades and is difficult to be reinvigorated with restored proliferative capacity. Here, we show that a half-life-extended interleukin-10–Fc fusion protein directly and potently enhanced expansion and effector function of terminally exhausted CD8+ tumor-infiltrating lymphocytes by promoting oxidative phosphorylation, a process that was independent of the progenitor exhausted T cells. Interleukin-10–Fc was a safe and highly efficient metabolic intervention that synergized with adoptive T cell transfer immunotherapy, leading to eradication of established solid tumors and durable cures in the majority of treated mice. These findings show that metabolic reprogramming by upregulating mitochondrial pyruvate carrier-dependent oxidative phosphorylation can revitalize terminally exhausted T cells and enhance the response to cancer immunotherapy.

DOI: 10.1038/s41590-021-00940-2

Source: https://www.nature.com/articles/s41590-021-00940-2