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Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling
Science ( IF 44.7 ) Pub Date : 2021-04-02 , DOI: 10.1126/science.aba1786
Evan W Weber 1 , Kevin R Parker 2 , Elena Sotillo 1 , Rachel C Lynn 1 , Hima Anbunathan 1 , John Lattin 1 , Zinaida Good 1, 3, 4 , Julia A Belk 5 , Bence Daniel 6 , Dorota Klysz 1 , Meena Malipatlolla 1 , Peng Xu 1 , Malek Bashti 1 , Sabine Heitzeneder 1 , Louai Labanieh 1 , Panayiotis Vandris 1 , Robbie G Majzner 1, 7 , Yanyan Qi 2 , Katalin Sandor 6 , Ling-Chun Chen 8 , Snehit Prabhu 1 , Andrew J Gentles 9 , Thomas J Wandless 8 , Ansuman T Satpathy 2, 3, 6 , Howard Y Chang 2, 3, 6, 10 , Crystal L Mackall 1, 3, 7, 11
Affiliation  

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.



中文翻译:


短暂休息通过表观遗传重塑恢复疲惫的 CAR-T 细胞的功能



T 细胞耗竭限制了针对癌症的免疫反应,也是嵌合抗原受体 (CAR)-T 细胞疗法产生耐药性的主要原因。使用小鼠异种移植模型和体外模型(其中强直 CAR 信号传导诱导衰竭的标志性特征),我们测试了受体信号传导短暂停止或休息对衰竭发生和维持的影响。通过使用药物调节系统强制下调 CAR 蛋白或使用多激酶抑制剂达沙替尼治疗来诱导休息,导致获得记忆样表型、全局转录和表观遗传重编程,并恢复耗尽的 CAR 的抗肿瘤功能。 T细胞。这项工作表明,休息可以通过预防或逆转疲劳来增强 CAR-T 细胞的功效,并且挑战了疲劳是一种表观遗传固定状态的观念。

更新日期:2021-04-02
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