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

基本信息

批准号：
10558744
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
项目类别：
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/10558744
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 Methylation Inhibition DNA Methyltransferase Inhibitor DNA Modification Methylases DNA methylation profiling DNMT3a Disease Epigenetic Process FDA approved Foundations Gene Expression Genes Genome HER2 inhibition Heritability Human Immune system Immunity Immunotherapy In Vitro Infiltration 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-Cell Activation 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 infiltrating T cells cancer type chimeric antigen receptor chimeric antigen receptor T cells chronic infection demethylating therapy 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

项目摘要

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这种保护是通过 T 细胞靶向并杀死肿瘤细胞或感染细胞的能力来实现的。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，如果抗原来源恢复，准备好快速回忆起它们的杀伤功能。细胞是长寿免疫力的基础，但是，如果疾病的根源没有得到初步清除，就会出现这样的情况。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 T 细胞介导的杀伤能力减少，通常称为 T 细胞耗竭。控制肿瘤进展的免疫系统是我们对 T 细胞理解的最新突破。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)，使 T 细胞介导的肿瘤控制发挥巨大作用。 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应用虽然 PD-1 阻断疗法明显控制肿瘤进展，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，该领域当前的挑战是识别非功能状态。我们最近证明了在 PD-1 治疗后维持 T 细胞耗竭的细胞固有特性。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 细胞耗竭我们发现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) 识别 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 DNA 甲基化程序。免疫检查点阻断 (ICB) 期间耗尽的 CD8 T 细胞 3) 确定 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这些研究将提供维持耗竭程序的细胞内在机制。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。