Chromatin remodeling in CD8+ T cells and harnessing stromal-immune interactions for effective antitumor immunity

CD8 T 细胞中的染色质重塑和利用基质免疫相互作用实现有效的抗肿瘤免疫

基本信息

批准号：
10530061
负责人：
Bryan McDonald
金额：
$ 3.94万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-14 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10530061
关键词：
Activities of Daily Living Acute Adopted Antigens Binding Binding Sites CD8-Positive T-Lymphocytes Cancer Patient Cell Communication Cell physiology Cells Cellular Immunology Chromatin Chromatin Remodeling Factor Chronic Clinical Complex Data Enhancers Epigenetic Process Exposure to Fellowship Fibroblasts Functional disorder Genetic Transcription Goals Growth Histones Host Defense Human Immune Immune mediated destruction Immune response Immune system Impairment Infection Knowledge Malignant Neoplasms Memory Mentors Mentorship Methods Mus Nucleosomes Pathology Play Postdoctoral Fellow Process Production Recording of previous events Research Research Training Role Scientist Series Signal Transduction Stromal Cells Structure Sucrose T cell differentiation T cell response T memory cell T-Lymphocyte Testing Therapeutic Therapeutic Intervention Training Transcriptional Regulation Tumor Immunity Vaccination Viral Cancer Virus Diseases Work Writing acute infection anti-PD1 antibodies antiviral immunity arm cancer care cancer type career chromatin remodeling chronic infection cytokine cytotoxic design effector T cell epigenome exhaust exhaustion experience experimental study fighting functional restoration immune checkpoint immune checkpoint blockade imprint improved inflammatory milieu lens pancreatic neoplasm pathogen pre-doctoral prevent progenitor programmed cell death protein 1 receptor response skill acquisition stem technique development tertiary lymphoid organ tool transcription factor tumor tumor immunology tumorigenic

项目摘要

Project Summary/Abstract Cytotoxic and antiviral cytokine production are hallmark effector functions of activated CD8+ T cells and are critical for combating pathogens and tumors, but these functional capacities can be lost during chronic infections and in cancer through a process called ‘T cell exhaustion’. Immune checkpoint blockade (ICB) therapies have emerged as powerful tools for restoring functionality in tumor-infiltrating CD8+ T cells, but unfortunately not all cancer patients benefit from these treatments. Therefore, a better understanding of mechanisms preventing immune-mediated destruction of tumors is needed in order to bring clinical benefit to all cancer patients. This proposal seeks to elaborate on two distinct mechanisms involved in promoting CD8+ T cell effector functions in cancer and chronic infection. In the F99 portion of this proposal, I investigate cell-intrinsic mechanisms of CD8+ T cell dysfunction through the lens of the SWI/SNF (a.k.a. BAF) chromatin remodeling complex to understand how the BAF complex sculpts chromatin accessibility and transcription factor binding as a CD8+ T cell differentiates into either functional effectors or into dysfunctional exhausted states. In the K00 portion, I propose to build upon my expertise in cellular immunology and T cell differentiation from my pre-doctoral work to pursue post-doctoral fellowship research in a more focused cancer immunology setting. I describe potential experiments and methods to investigate the role of cancer-associated fibroblasts (CAFs) in the formation and maturation of tertiary lymphoid structures (TLS), aggregates of immune and stromal cells in tumors that form a unique microenvironmental niche to support antitumor immune cell function, including sustaining CD8+ T cell responses. I will also study how different types of CAFs interact with T cells in tumors to regulate their functional and differentiation states, for example if CAFs within TLSs actually prevent terminal CD8+ T cell exhaustion. The goal of these studies is to better understand how modulating CAF-T cell interactions or TLS formation in tumors can enhance CD8+ T cell functions and responsiveness to ICB. This application details my training plan including research mentorship, training in new techniques, and development of skills in scientific professionalism, writing, presentation of data, and identification of a post-doctoral mentor. The research and training outlined in this application will prepare me to pursue a career in academic research as an independent scientist in the cancer immunology field.

项目摘要/摘要细胞毒性和抗病毒细胞因子的产生是活化的CD8+ T细胞的标志性效应子功能，并且是对于梳理病原体和肿瘤至关重要，但是在慢性感染期间可能会丧失这些功能能力在癌症中，通过称为“ T细胞耗尽”的过程。免疫检查点封锁（ICB）疗法具有成为恢复肿瘤浸润CD8+ T细胞功能的强大工具，但不幸的是不是全部癌症患者受益于这些治疗。因此，更好地理解防止机制为了为所有癌症患者带来临床益处，需要进行免疫介导的肿瘤破坏。这提案旨在详细阐述促进CD8+ T细胞效应子功能的两种不同的机制癌症和慢性感染。在该提案的F99部分中，我研究了CD8+的细胞内部机制通过SWI/SNF（又称BAF）染色质重塑复合物的T细胞功能障碍 BAF复合物如何雕刻染色质的可及性和转录因子结合为CD8+ T细胞区分功能效应或耗尽功能失调的状态。在K00部分中，我提出了基于我在我的博物前工作中的细胞免疫学和T细胞分化方面的专业知识以购买在更重点的癌症免疫学环境中，博士后奖学金研究。我描述了潜在的实验以及研究癌症相关成纤维细胞（CAF）在形成和成熟中的作用的方法肿瘤中的免疫细胞和基质细胞的三级淋巴结构（TLS），形成独特的微环境利基市场支持抗肿瘤免疫细胞功能，包括维持CD8+ T细胞反应。我还将研究不同类型的CAF如何与肿瘤中的T细胞相互作用以调节其功能和分化状态，例如，如果TLSS中的CAFS实际上可以防止末端CD8+ T细胞耗尽。目标这些研究是更好地了解肿瘤中如何调节CAF-T细胞相互作用或TLS形成如何增强CD8+ T细胞功能和对ICB的响应能力。此应用程序详细介绍了我的培训计划，包括研究心态，新技术的培训以及科学专业，写作技能的发展数据的呈现，并识别博士后心理。概述的研究和培训应用程序将使我为作为癌症的独立科学家从事学术研究的职业做好准备免疫学领域。