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

项目摘要/摘要 细胞毒和抗病毒细胞因子的产生是激活的CD8+T细胞的标志性效应功能，并 对于对抗病原体和肿瘤至关重要，但在慢性感染期间，这些功能可能会丧失 在癌症中，通过一种被称为T细胞耗尽的过程。免疫检查点阻断(ICB)疗法有 成为恢复肿瘤浸润性CD8+T细胞功能的有力工具，但不幸的是，并不是所有 癌症患者从这些治疗中受益。因此，更好地理解预防机制 为了给所有癌症患者带来临床上的好处，需要免疫介导的肿瘤破坏。这 该提案旨在阐述促进CD8+T细胞效应器功能的两种不同机制 癌症和慢性感染。在这项提案的F99部分，我研究了CD8+的细胞内在机制 T细胞功能障碍通过SWI/SNF的晶状体(又名了解染色质重塑复合体 BAF复合体作为CD8+T细胞如何塑造染色质可及性和转录因子结合 分化为功能效应器或功能失调的疲惫状态。在K00部分，我建议 从我的博士前工作中积累我在细胞免疫学和T细胞分化方面的专业知识来从事 在更专注于癌症免疫学的背景下进行博士后研究。我描述了潜在的实验 以及研究癌症相关成纤维细胞(CAF)在肿瘤形成和成熟中的作用的方法 三级淋巴结构(TLS)，肿瘤中免疫细胞和基质细胞的聚集体，形成独特的 支持抗肿瘤免疫细胞功能的微环境，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，以调节它们的功能和 分化状态，例如，如果TLS内的CAF实际上阻止了终末CD8+T细胞耗尽。目标是 这些研究的一部分是为了更好地了解如何调节肿瘤中CAF-T细胞相互作用或TLS的形成 增强CD8+T细胞功能和对ICB的反应性。这份申请详细说明了我的培训计划，包括 研究指导，新技术培训，科学专业技能的发展，写作， 提供数据，并确定博士后导师。其中概述的研究和培训 申请将使我做好准备，从事学术研究，成为癌症领域的一名独立科学家 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.