瑞士洛桑大学Ping-Chih Ho研究团队在研究中取得进展。他们提出CD8 + 肿瘤浸润性T淋巴细胞（TIL）中线粒体动力学紊乱可促进T细胞衰竭。该研究于2020年10月5日发表于国际一流学术期刊《自然-免疫学》。

他们发现，由于线粒体活性的降低，TILs积累了去极化的线粒体，并显示出最终衰竭的T细胞功能、转录组和表观遗传学特征。从机制上讲，TILs的线粒体适应性降低是由T细胞受体刺激，微环境应激源和PD-1信号传导的协同作用引起的。用药理学抑制剂强行去极化线粒体积累，导致表观遗传重编程趋向终极衰竭，表明线粒体失调导致T细胞衰竭。

此外，补充烟酰胺核糖可增强T细胞线粒体适应性，并提高对抗PD-1治疗的反应性。总之，他们的结果揭示了线粒体动力学和质量如何协调T细胞抗肿瘤反应以及对衰竭程序的应答。

研究人员表示，肿瘤中出现的代谢挑战减弱了TIL的代谢适应性和抗肿瘤活性。然而，目前尚不清楚是否持续的代谢功能不全，可导致永久性T细胞功能障碍。

附：英文原文

Title: Disturbed mitochondrial dynamics in CD8 + TILs reinforce T cell exhaustion

Author: Yi-Ru Yu, Hana Imrichova, Haiping Wang, Tung Chao, Zhengtao Xiao, Min Gao, Marcela Rincon-Restrepo, Fabien Franco, Raphael Genolet, Wan-Chen Cheng, Camilla Jandus, George Coukos, Yi-Fan Jiang, Jason W. Locasale, Alfred Zippelius, Pu-Ste Liu, Li Tang, Christoph Bock, Nicola Vannini, Ping-Chih Ho

Issue&Volume: 2020-10-05

Abstract: The metabolic challenges present in tumors attenuate the metabolic fitness and antitumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulated depolarized mitochondria as a result of decreased mitophagy activity and displayed functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, reduced mitochondrial fitness in TILs was induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signaling. Enforced accumulation of depolarized mitochondria with pharmacological inhibitors induced epigenetic reprogramming toward terminal exhaustion, indicating that mitochondrial deregulation caused T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal insights into how mitochondrial dynamics and quality orchestrate T cell antitumor responses and commitment to the exhaustion program. Ho and colleagues report that mitochondrial dysfunction and impaired mitophagy triggered by the tumor microenvironment lead to subsequent epigenetic changes and cause permanent T cell exhaustion and dysfunction.

DOI: 10.1038/s41590-020-0793-3

Source: https://www.nature.com/articles/s41590-020-0793-3