德国肿瘤生物学与实验治疗研究所Florian R. Greten团队近期取得重要工作进展，他们研究发现Urolithin A诱导的线粒体自噬促进具有强抗肿瘤免疫T记忆干细胞的扩增。相关研究成果2022年10月18日在线发表于《免疫》杂志上。

据介绍，T记忆干细胞（T_SCM）表现出增强的自我更新和延长的生存能力，它们阻止T细胞衰竭，促进有效的抗肿瘤T细胞反应。T_SCM细胞可以通过Urolithin A（UA）扩增，UA是由富含鞣花草素的食物中的共生肠道微生物组产生的，已知可以改善线粒体健康。口服UA给荷瘤小鼠提供了强大的抗肿瘤CD8⁺ T细胞免疫，而体外UA预处理的T细胞在过继细胞转移后显示出更好的抗肿瘤功能。UA诱导的T_SCM的形成依赖于pink1介导的自噬触发线粒体磷酸酶Pgam5的胞质释放。胞质Pgam5去磷酸化β-catenin，驱动Wnt信号通路和代偿线粒体生物发生。

总之，研究人员揭示了一个连接自噬和T_SCM形成的关键信号通路，并认为耐受性良好的代谢化合物UA是改善免疫治疗的一个值得尝试的选择。

附：英文原文

Title: Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy

Author: Dominic Denk, Valentina Petrocelli, Claire Conche, Moritz Drachsler, Paul K. Ziegler, Angela Braun, Alena Kress, Adele M. Nicolas, Kathleen Mohs, Christoph Becker, Markus F. Neurath, Henner F. Farin, Christian J. Buchholz, Pénélope A. Andreux, Chris Rinsch, Florian R. Greten

Issue&Volume: 2022-10-18

Abstract: T memory stem cells (TSCM) display increased self-renewal and prolonged survival capabilities, thus preventing T cell exhaustion and promoting effective anti-tumor T cell responses. TSCM cells can be expanded by Urolithin A (UA), which is produced by the commensal gut microbiome from foods rich in ellagitannins and is known to improve mitochondrial health. Oral UA administration to tumor-bearing mice conferred strong anti-tumor CD8+ T cell immunity, whereas ex vivo UA pre-treated T cells displayed improved anti-tumor function upon adoptive cell transfer. UA-induced TSCM formation depended on Pink1-mediated mitophagy triggering cytosolic release of the mitochondrial phosphatase Pgam5. Cytosolic Pgam5 dephosphorylated β-catenin, which drove Wnt signaling and compensatory mitochondrial biogenesis. Collectively, we unravel a critical signaling pathway linking mitophagy to TSCM formation and suggest that the well-tolerated metabolic compound UA represents an attractive option to improve immune therapy.

DOI: 10.1016/j.immuni.2022.09.014

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00508-8