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

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.