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细胞是免疫系统的关键部分，可防止细胞内病原体和癌症。 T细胞的靶向和杀死肿瘤细胞或感染A的细胞的能力来实现此保护病原。清除分离的细胞后，病原体特异性的CD8 T细胞可以持续宿主的寿命，如果抗原返回的来源，准备快速回忆起他们的杀戮功能。这种中毒的记忆状态t 细胞是长寿命免疫的基础。但是，如果最初未清除该疾病的根源，则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少，通常称为T细胞耗尽。 T细胞介导的杀戮的减少限制了控制肿瘤进展的免疫系统。我们对T细胞的理解的最新突破疲惫表明，非功能状态可以通过阻止的疗法暂时逆转 T细胞上的受体信号传导（PD-1），使T细胞介导的肿瘤对照。鉴于巨大 PD-1封锁对控制肿瘤进展的治疗效应，FDA最近批准了它临床用途。虽然PD-1阻滞治疗清楚地控制了肿瘤的进展，但临时重新激活CD8 T细胞保留对非功能状态的记忆。因此，该领域的当前挑战是确定 PD-1处理后，保持T细胞耗尽的细胞中性特性。我们最近证明了表观遗传修饰（对细胞分裂过程中维持的基因组的修饰）在此期间获得长时间的抗原暴露通过维持疲劳特异性基因表达来增强T细胞的衰竭程序。我们假设这些表观遗传学计划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，我们提案的目的是1）确定DE NOVO DNA甲基化程序，增强小鼠和人类T细胞耗尽的承诺肿瘤特异性CD8 T细胞。 2）擦除从头DNA甲基化计划，以限制修订在免疫检查点阻滞（ICB）期间耗尽的CD8 T细胞的。 3）确定汽车T细胞是否疲惫受到从头DNA甲基化的调节。这里提出的研究将广泛识别基因抗原特异性CD8 T细胞中抑制抗肿瘤功能的表达程序，并将提供新的见解进入维持精疲力竭程序的细胞中心机制。这些研究将提供开发方法的基础，以重新编程耗尽的CD8 T细胞，以在和免疫检查点封锁和汽车T细胞疗法后。