Epigenetic Reprogramming of T cell Exhaustion To Enhance Tumor Immunotherapy

T 细胞耗竭的表观遗传重编程增强肿瘤免疫治疗

• 批准号: 10337284
• 负责人: Benjamin Alan Youngblood
• 金额: $ 40.24万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337284
• 关键词: Affinity; Antigen Presentation; Antigen-Presenting Cells; Antigens; Antitumor Response; Autoimmunity; CAR T cell therapy; CD19 gene; CD8-Positive T-Lymphocytes; Cell Maintenance; Cell division; Cells; Cellular immunotherapy; Chronic; Clinical; Coupled; Cross Presentation; DNA; DNA Methylation; DNA Methyltransferase Inhibitor; DNA Modification Methylases; DNA methylation profiling; DNMT3a; Disease; Epigenetic Process; FDA approved; Foundations; Gene Expression; Genes; Genome; Heritability; Human; Immune system; Immunity; Immunotherapy; In Vitro; Life; Light; Longevity; Lymphoid Tissue; Maintenance; Malignant Neoplasms; Measures; Mediating; Memory; Methods; Methylation; Modification; Mus; Mutation; Myeloid Cells; PD-1 blockade; Patients; Property; Psychological reinforcement; Receptor Signaling; Rejuvenation; Reporter; Reporting; Repression; Research; Signal Transduction; Solid Neoplasm; Source; System; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Effect; Transcriptional Regulation; Transgenic Organisms; Translating; Tumor Immunity; Virus; Virus Diseases; Vitiligo; Work; anti-tumor immune response; bisulfite sequencing; cancer type; chimeric antigen receptor; chimeric antigen receptor T cells; chronic infection; demethylation; effector T cell; exhaust; exhaustion; immune checkpoint blockade; improved; in vivo; inhibitor; insight; knock-down; lymphoid neoplasm; monocyte; neoplasm immunotherapy; neoplastic cell; novel strategies; pathogen; pediatric patients; preservation; prevent; programmed cell death protein 1; programs; promoter; receptor; response; success; tumor; tumor microenvironment; tumor progression; whole genome

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.

摘要：CD8 T 细胞是免疫系统的重要组成部分，可防御细胞内病原体和 癌症。这种保护是通过 T 细胞靶向并杀死肿瘤细胞或感染病毒的细胞的能力来实现的。 病原。在清除患病细胞后，病原体特异性 CD8 T 细胞可以在宿主的一生中持续存在， 如果抗原来源返回，准备好快速恢复其杀伤功能。这种稳定的记忆状态 T 细胞是长期免疫的基础。然而，如果最初没有清除疾病的来源，就会发生这样的情况 在慢性感染或癌症期间，病原体特异性 CD8 T 细胞的杀伤功能逐渐减弱 减少，通常称为 T 细胞耗竭。 T 细胞介导的杀伤作用的减少限制了 免疫系统控制肿瘤进展。我们对 T 细胞认识的最新突破 疲惫已经表明，非功能状态可以通过阻断疗法暂时逆转 T 细胞上的受体信号传导 (PD-1)，实现 T 细胞介导的肿瘤控制。鉴于巨大的 PD-1阻断剂对控制肿瘤进展具有治疗作用，FDA最近批准其用于 临床使用。虽然 PD-1 阻断疗法明显控制了肿瘤进展，但暂时重新激活的 CD8 T 细胞保留非功能状态的记忆。因此，该领域当前的挑战是确定 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（在细胞分裂过程中维持的基因组修饰） 长时间的抗原暴露通过维持耗竭特异性基因表达来增强 T 细胞耗竭 程序。我们假设这些表观遗传程序是治疗策略的主要障碍 旨在重新编程耗尽的肿瘤特异性 T 细胞。因此，我们建议的目标是 1) 确定 de novo DNA 甲基化程序可增强小鼠和人类 T 细胞耗竭的承诺 肿瘤特异性 CD8 T 细胞。 2) 消除限制再生的从头 DNA 甲基化程序 免疫检查点阻断 (ICB) 期间耗尽的 CD8 T 细胞。 3) 判断是否为CAR T细胞 耗竭是由DNA从头甲基化调节的。这里提出的研究将广泛识别基因 抑制抗肿瘤功能的抗原特异性 CD8 T 细胞中的表达程序将提供新的见解 进入维持耗竭程序的细胞内在机制。这些研究将提供 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了基础 免疫检查点阻断和 CAR T 细胞疗法后。