Epigenetic Reprogramming of T cell Exhaustion To Enhance Tumor Immunotherapy

摘要：CD8 T细胞是免疫系统的重要组成部分，可抵御细胞内病原体和 癌症。这种保护是通过T细胞靶向并杀死肿瘤细胞或感染了 病原体。一旦病细胞被清除，病原体特异性CD8T细胞可以在宿主的生命中持续存在， 准备好在抗原源返回时迅速召回它们的杀戮功能。存储器T的这种稳定状态 细胞是长寿免疫的基础。然而，如果最初没有清除疾病的根源，就会发生 在慢性感染或癌症期间，病原体特异性CD8 T细胞的杀伤功能是递增的 减少，通常被称为T细胞衰竭。这种T细胞介导的杀伤作用的减少限制了 控制肿瘤进展的免疫系统。我们对T细胞认识的最新突破 疲惫表明，非功能状态可以通过阻断的治疗暂时逆转 T细胞上的受体信号(PD-1)，使T细胞介导的肿瘤控制。鉴于巨大的 PD-1阻滞剂在控制肿瘤进展方面的疗效，FDA最近批准其用于 临床应用。虽然PD-1阻断治疗明显控制了肿瘤的进展，但暂时重新激活的CD8 T细胞保留了非功能状态的记忆。因此，该领域目前面临的一个挑战是确定 PD-1治疗后维持T细胞耗竭的细胞固有特性。我们最近证明了 表观遗传修饰(在细胞分裂过程中保持的对基因组的修改)在 长期抗原暴露通过维持力竭特异性基因的表达来加强T细胞的耗竭 程序。我们假设这些表观遗传程序是治疗策略的主要障碍 目的对耗尽的肿瘤特异性T细胞进行重新编程。因此，我们建议的目的是1)确定 在小鼠和人类中强化T细胞耗竭承诺的新DNA甲基化计划 肿瘤特异性CD8T细胞。2)消除限制返老还童的从头DNA甲基化程序 在免疫检查点阻断(ICB)期间耗尽的CD8T细胞的数量。3)确定CAR T细胞 疲劳是由从头开始的DNA甲基化来调节的。这里提出的研究将广泛地识别基因 在抗原特异性CD8 T细胞中抑制抗肿瘤功能的表达程序，将提供新的见解 进入细胞内维持耗竭程序的内在机制。这些研究将提供一个 为开发重新编程耗尽的CD8 T细胞以维持效应潜力的方法奠定基础 在免疫检查站封锁和CAR T细胞治疗之后。

SUMMARY: CD8 T cells are a critical part of the immune system that protect against intracellular pathogens and cancer. This protection is achieved by the T cell’s ability to target and kill tumor cells or cells infected with a pathogen. Upon clearance of the diseased cells, pathogen-specific CD8 T cells can persist for the life of the host, ready to rapidly recall their killing functions if the source of the antigen returns. This poised state of memory T cells is the basis for long-lived immunity. However, if the source of the disease is not initially cleared, as occurs during chronic infections or cancers, the killing functions of pathogen-specific CD8 T cells are progressively reduced, commonly referred to as T cell exhaustion. This reduction in T cell mediated killing limits the ability of the immune system to control tumor progression. Recent breakthroughs in our understanding of T cell exhaustion have revealed that the non-functional state can be temporarily reversed by therapies that block receptor signaling (PD-1) on the T cell, enabling T cell mediated tumor control. In light of the tremendous therapeutic effect PD-1 blockade has on controlling tumor progression, the FDA has recently approved it for clinical use. While PD-1 blockade therapy clearly controls tumor progression, the temporarily reactivated CD8 T cells retain a memory of the non-functional state. Therefore, a current challenge for the field is to identify the cell-intrinsic properties that maintain T cell exhaustion after PD-1 treatment. We have recently demonstrated that epigenetic modifications (modifications to the genome that are maintained during cell division) acquired during prolonged antigen exposure reinforces T cell exhaustion by maintaining exhaustion-specific gene expression programs. We hypothesize that these epigenetic programs are a major barrier for therapeutic strategies that aim to reprogram exhausted tumor-specific T cells. Therefore, the aims of our proposal are 1) To identify de novo DNA methylation programs that reinforce commitment of T cell exhaustion in mouse and human tumor-specific CD8 T cells. 2) To erase de novo DNA methylation programs that constrain rejuvenation of exhausted CD8 T cells during immune checkpoint blockade (ICB). 3) To determine if CAR T cell exhaustion is regulated by de novo DNA methylation. The research proposed here will broadly identify gene expression programs in antigen-specific CD8 T cells that inhibit anti-tumor functions, and will provide new insight into the cell-intrinsic mechanisms for maintenance of exhaustion programs. These studies will provide a foundation for developing methods to reprogram exhausted CD8 T cells to sustain effector potential during and after immune checkpoint blockade and CAR T-cell therapies.