Chimeric antigen receptor (CAR) T cell therapy is revolutionizing cancer immunotherapy for patients with B cell malignancies and is now being developed for solid tumors and chronic viral infections. Although clinical trials have demonstrated the curative potential of CAR T cell therapy, a substantial and well-established limitation is the heightened contraction and transient persistence of CAR T cells during prolonged antigen exposure. The underlying mechanism(s) for this dysfunctional state, often termed CAR T cell exhaustion, remains poorly defined. Here, we report that exhaustion of human CAR T cells occurs through an epigenetic repression of the T cell’s multipotent developmental potential. Deletion of the de novo DNA methyltransferase 3 alpha (DNMT3A) in T cells expressing first- or second-generation CARs universally preserved the cells’ ability to proliferate and mount an antitumor response during prolonged tumor exposure. The increased functionality of the exhaustion-resistant DNMT3A knockout CAR T cells was coupled to an up-regulation of interleukin-10, and genome-wide DNA methylation profiling defined an atlas of genes targeted for epigenetic silencing. This atlas provides a molecular definition of CAR T cell exhaustion, which includes many transcriptional regulators that limit the “stemness” of immune cells, including CD28, CCR7, TCF7, and LEF1. Last, we demonstrate that this epigenetically regulated multipotency program is firmly coupled to the clinical outcome of prior CAR T cell therapies. These data document the critical role epigenetic mechanisms play in limiting the fate potential of human T cells and provide a road map for leveraging this information for improving CAR T cell efficacy.

中文翻译：

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删除 CAR T 细胞中的 DNMT3A 可防止衰竭并增强抗肿瘤活性


嵌合抗原受体 (CAR) T 细胞疗法正在彻底改变 B 细胞恶性肿瘤患者的癌症免疫疗法，目前正在开发用于实体瘤和慢性病毒感染的疗法。尽管临床试验已经证明了 CAR T 细胞疗法的治疗潜力，但一个实质性且明确的限制是 CAR T 细胞在长时间抗原暴露期间会增强收缩和短暂持续。这种功能失调状态的潜在机制（通常称为 CAR T 细胞耗竭）仍然不明确。在这里，我们报告说，人类 CAR T 细胞的耗竭是通过 T 细胞多能发育潜力的表观遗传抑制而发生的。表达第一代或第二代 CAR 的 T 细胞中从头 DNA 甲基转移酶 3 α (DNMT3A) 的缺失普遍保留了细胞在长时间肿瘤暴露期间增殖和产生抗肿瘤反应的能力。抗耗竭性 DNMT3A 敲除 CAR T 细胞的功能增强与白细胞介素 10 的上调相结合，全基因组 DNA 甲基化分析定义了表观遗传沉默的基因图谱。该图谱提供了 CAR T 细胞耗竭的分子定义，其中包括许多限制免疫细胞“干性”的转录调节因子，包括 CD28、CCR7、TCF7 和 LEF1。最后，我们证明这种表观遗传调控的多能性计划与先前 CAR T 细胞疗法的临床结果紧密结合。这些数据记录了表观遗传机制在限制人类 T 细胞命运潜力方面发挥的关键作用，并为利用这些信息提高 CAR T 细胞功效提供了路线图。