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

项目概要/摘要 细胞毒性和抗病毒细胞因子的产生是活化的CD 8 + T细胞的标志性效应子功能， 这对于对抗病原体和肿瘤至关重要，但这些功能性能力在慢性感染期间可能会丧失。 而在癌症中则是通过一个称为“T细胞耗竭”的过程。免疫检查点阻断（ICB）疗法 作为恢复肿瘤浸润性CD 8 + T细胞功能的有力工具，但不幸的是，并非所有 癌症患者受益于这些治疗。因此，更好地了解预防机制， 为了给所有癌症患者带来临床益处，需要免疫介导的肿瘤破坏。这 一项提案试图详细阐述两种不同的机制，涉及促进CD 8 + T细胞效应功能， 癌症和慢性感染。在本提案的F99部分，我研究了CD 8 + T细胞的细胞内在机制。 通过SWI/SNF的透镜的T细胞功能障碍（也称为BAF）染色质重塑复合物来了解 BAF复合体如何塑造染色质可及性和转录因子结合为CD 8 + T细胞 区分为功能性效应器或功能失调的疲惫状态。在K 00部分，我建议 我在细胞免疫学和T细胞分化方面的专业知识， 博士后奖学金研究在一个更集中的癌症免疫学设置。我描述了潜在的实验 以及研究癌症相关成纤维细胞（CAF）在肿瘤形成和成熟中的作用的方法。 三级淋巴样结构（TLS），肿瘤中免疫和基质细胞的聚集体， 微环境生态位，以支持抗肿瘤免疫细胞功能，包括维持CD 8 + T细胞应答。 我还将研究不同类型的CAFs如何与肿瘤中的T细胞相互作用，以调节其功能和免疫功能。 例如，如果TLS内的CAF实际上阻止了终末CD 8 + T细胞耗竭，则可以在分化状态下检测到CAF。目标 这些研究的目的是更好地了解调节肿瘤中CAF-T细胞相互作用或TLS形成如何 增强CD 8 + T细胞功能和对ICB的反应性。此应用程序详细说明了我的培训计划，包括 研究指导，新技术培训，科学专业技能发展，写作， 介绍数据，并确定博士后导师。本报告中概述的研究和培训 申请将准备我追求的职业生涯在学术研究作为一个独立的科学家在癌症 免疫学领域。

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.