Epigenetic Reprogramming of T cell Exhaustion To Enhance Tumor Immunotherapy

概述：CD 8 T细胞是免疫系统的关键部分，其保护免受细胞内病原体的侵害， 癌这种保护作用是通过T细胞靶向和杀死肿瘤细胞或感染肿瘤细胞的细胞的能力来实现的。 病原体在清除病变细胞后，病原体特异性CD 8 T细胞可以持续宿主的生命， 一旦抗原来源恢复，它们就会迅速恢复杀伤功能。这种平静的记忆状态 细胞是长期免疫的基础。然而，如果疾病的源头最初没有被清除， 在慢性感染或癌症期间，病原体特异性CD 8 T细胞的杀伤功能逐渐减弱， 减少，通常称为T细胞耗竭。T细胞介导的杀伤的这种减少限制了免疫调节的能力。 免疫系统来控制肿瘤的发展。我们对T细胞认识的最新突破 已经发现，非功能性状态可以暂时逆转的治疗， 受体信号传导（PD-1）的T细胞，使T细胞介导的肿瘤控制。鉴于巨大的 PD-1阻断对控制肿瘤进展的治疗作用，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进展，但暂时再活化的CD 8 T细胞保留了非功能状态的记忆。因此，该领域目前的挑战是确定 细胞内在特性，在PD-1治疗后维持T细胞耗竭。我们最近已经证明， 表观遗传修饰（在细胞分裂过程中维持的基因组修饰）， 延长抗原暴露通过维持耗竭特异性基因表达增强T细胞耗竭 程序.我们假设这些表观遗传学程序是治疗策略的主要障碍， 旨在重新编程耗尽的肿瘤特异性T细胞。因此，我们的建议的目的是1）识别de 在小鼠和人类中加强T细胞耗竭的新DNA甲基化程序 肿瘤特异性CD 8 T细胞。2)删除限制年轻化的从头DNA甲基化程序 免疫检查点阻断（ICB）期间耗尽的CD 8 T细胞。3)为了确定CAR T细胞是否 耗竭受从头DNA甲基化调节。本文提出的研究将广泛地确定基因 在抗原特异性CD 8 T细胞中的表达程序，抑制抗肿瘤功能，并将提供新的见解 进入细胞内在的机制，以维持耗竭程序。这些研究将提供一个 为开发重编程耗尽的CD 8 T细胞以维持细胞周期中的效应子潜能的方法奠定了基础， 免疫检查点阻断和CAR T细胞疗法后。

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.