Dissecting the enhancer logic governing immune cell fate decisions

剖析控制免疫细胞命运决定的增强子逻辑

• 批准号: 10472872
• 负责人: Debattama Rai Sen
• 金额: $ 151.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472872
• 关键词: Address; Antitumor Response; Atlases; Automobile Driving; Biological Assay; CD8-Positive T-Lymphocytes; Cells; Chromatin; Chronic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Disease; Enhancers; Epigenetic Process; Functional disorder; Goals; Immune; Immunity; Immunobiology; Knock-in; Logic; Malignant Neoplasms; Pattern; Phenotype; Play; Pre-Clinical Model; Primary carcinoma of the liver cells; Process; Role; Shapes; Signal Pathway; Signal Transduction; T cell differentiation; T cell regulation; T cell therapy; T-Lymphocyte; Technology; Therapeutic; Tissues; Tumor Immunity; Virus Diseases; cancer immunotherapy; cell fate specification; epigenome editing; exhaust; gain of function; immune checkpoint blockade; improved outcome; in vivo; insight; loss of function; melanoma; novel; progenitor; tumor; tumor immunology; tumor microenvironment

Project Summary CD8 T cells are a critical component of an effective anti-tumor response. Therefore, a major goal in cancer immunology, and more broadly in immunobiology, has been to understand how specific disease contexts govern T cell fate and function. A growing and largely descriptive atlas of chromatin accessibility has begun providing rich insight into the epigenetic landscape of CD8 T cells, yet it remains a challenge to understand cause-and-effect relationships from such data. Furthermore, T cell fate specification, like many cellular differentiation processes, develops with a continuum of phenotypic and functional intermediate states. This prompts the question, which epigenetic mechanisms are causal in driving state transitions within CD8 T cells? What are the earliest signaling pathways that drive commitment to particular T cell phenotype? How does tissue context shape anti-tumor T cell immunity? Our proposal addresses these questions by leveraging loss- of-function (LOF) and gain-of-function (GOF) approaches for enhancer editing to identify how, when and where CD8 T cell fate commitment happens in vivo. As an initial application, we will use this framework to understand the context-specific epigenetic mechanisms governing exhausted CD8 T cell differentiation in the tumor microenvironment. We focus in particular on comparing progenitor exhausted T cells in melanoma vs. hepatocellular carcinoma since these two diseases have markedly different tissue-specific signaling, have differential responsivity to immune checkpoint blockade, and most importantly, induce both shared and tumor- specific patterns of epigenetic changes. Although this project will yield fundamental insights into T cell regulation, we also aim to extend epigenetic reprogramming to preclinical models of adoptive T cell therapy with potential therapeutic application. The novel integration of technologies to achieve these goals promises to be useful for diverse disease contexts where CD8 T cells play a role, in cancer and beyond.

项目总结