Defining molecular determinants of T cell spatial localization and clonal response throughout PDAC malignant progression 3030

Abstract Description Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, poised to become the second leading cause of cancer-related deaths in North America. The paucity of neoantigen presentation in PDAC has been hypothesized to promote the development of an “immunologically-cold” tumor microenvironment (TME), driving poor clinical responses to immunotherapy. Despite the abundant immune infiltrate observed in PDAC, T cells display a limited cytotoxic capacity to kill malignant tumor cells which further diminishes throughout disease progression. Utilizing single cell RNA-sequencing coupled to T cell receptor profiling, we have characterized T cell populations in clinical specimens of inflammatory pre-malignant intraductal papillary mucinous neoplasia (IPMN) lesions and advanced stage PDAC tumors. Striking phenotypic and clonal dynamic differences were observed in both CD8 and CD4 T cell populations between IPMN and PDAC specimens which underly their distinct functional capabilities in the evolving TME. The spatial interactions and microenvironmental neighborhoods of neoantigen-reactive T cells in PDAC have yet to be explored in-depth and hold unexploited therapeutic potential. Utilizing the 10X Genomics Xenium platform with custom probes designed to hybridize with neo-antigen-specific T cell clones, we are interrogating the cellular interactions which drive T cell clonal expansion to identify therapeutically relevant vulnerabilities in PDAC malignant progression. Funding Sources Supported by National Insitutes of Health, Canadian Institutes of Health Research, and Princess Margaret Cancer Center Catalyst Grant. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)