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

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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.