美国斯坦福大学医学院Crystal L. Mackall研究组的最新研究表明，短暂的静止可以通过表观遗传重塑恢复耗竭嵌合抗原受体（CAR）-T细胞的功能。相关论文发表在2021年4月2日出版的《科学》杂志上。

使用鼠类异种移植模型和药物诱导CAR信号衰竭的体外模型，研究人员测试了受体信号传导暂时停止或静止对T细胞耗竭发展和维持的影响。通过使用可调节给药系统或使用多激酶抑制剂达沙替尼减弱CAR蛋白表达来诱导休眠可产生获得记忆样表型、整体转录和表观遗传重编程并恢复了耗竭CAR- T细胞的功能。

这项工作表明，静止可以通过预防或逆转衰竭来增强CAR-T细胞的功效，并且对衰竭是一种表观遗传固定状态的观念提出了挑战。

据介绍，T细胞耗竭限制了靶向癌症的免疫反应，这也是对CAR-T细胞疗法产生耐药的主要原因。

附：英文原文

Title: Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling

Author: Evan W. Weber, Kevin R. Parker, Elena Sotillo, Rachel C. Lynn, Hima Anbunathan, John Lattin, Zinaida Good, Julia A. Belk, Bence Daniel, Dorota Klysz, Meena Malipatlolla, Peng Xu, Malek Bashti, Sabine Heitzeneder, Louai Labanieh, Panayiotis Vandris, Robbie G. Majzner, Yanyan Qi, Katalin Sandor, Ling-Chun Chen, Snehit Prabhu, Andrew J. Gentles, Thomas J. Wandless, Ansuman T. Satpathy, Howard Y. Chang, Crystal L. Mackall

Issue&Volume: 2021/04/02

Abstract: T cell exhaustion limits immune responses against cancer and is a major cause of resistance to chimeric antigen receptor (CAR)–T cell therapeutics. Using murine xenograft models and an in vitro model wherein tonic CAR signaling induces hallmark features of exhaustion, we tested the effect of transient cessation of receptor signaling, or rest, on the development and maintenance of exhaustion. Induction of rest through enforced down-regulation of the CAR protein using a drug-regulatable system or treatment with the multikinase inhibitor dasatinib resulted in the acquisition of a memory-like phenotype, global transcriptional and epigenetic reprogramming, and restored antitumor functionality in exhausted CAR-T cells. This work demonstrates that rest can enhance CAR-T cell efficacy by preventing or reversing exhaustion, and it challenges the notion that exhaustion is an epigenetically fixed state.

DOI: 10.1126/science.aba1786

Source: https://science.sciencemag.org/content/372/6537/eaba1786