Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA.
Science. 2021 Apr 2;372(6537). doi: 10.1126/science.aba1786.
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.
T 细胞耗竭限制了针对癌症的免疫反应，是对嵌合抗原受体 (CAR)-T 细胞治疗产生耐药性的主要原因。使用鼠异种移植模型和体外模型，其中持续的 CAR 信号诱导衰竭的标志性特征，我们测试了受体信号短暂停止，或休息，对衰竭的发展和维持的影响。通过使用药物调控系统强制下调 CAR 蛋白或用多激酶抑制剂 dasatinib 治疗来诱导休息，导致获得类似记忆的表型、全转录组和表观遗传重编程，并恢复衰竭的 CAR-T 细胞的抗肿瘤功能。这项工作表明，通过防止或逆转衰竭，休息可以增强 CAR-T 细胞的疗效，并挑战了衰竭是一种表观遗传固定状态的观点。
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