PROJECT SUMMARY This proposal describes a five-year plan involving career development, didactic training, and basic research focused on mechanisms of immune evasion in pancreatic cancer, which will facilitate the independent physician scientist career of Dr. Mark Diamond in the area of cancer immunology. The candidate is interested in understanding barriers to effective antitumor immunity against pancreatic ductal adenocarcinoma (PDAC), a deadly cancer that is poorly T cell-infiltrated and refractory to current immunotherapy. Using tumors derived from the ‘KPC’ murine model, Dr. Diamond has shown that PDAC cells engineered to be highly antigenic exhibit selective immune escape in the pancreatic and peritoneal microenvironments; and that outgrowth resulted from poor tumor-specific T cell priming by classical dendritic cells (cDCs) rather than antigen loss or tumor immunoediting. He has additionally modeled acquired resistance following combination immunotherapy of subcutaneous tumors, as prior studies have demonstrated the efficacy of CD40 agonist-based regimens that promote T cell priming and can induce durable regressions. Studying late tumor recurrences following complete responses to therapy, the candidate has shown that such tumors exhibit acquired immunotherapy resistance and upregulation of genes in the epithelial-mesenchymal transition (EMT) pathway. Based on these data, Dr. Diamond hypothesizes that antitumor immunity to PDAC is limited by both tumor-cell intrinsic processes including EMT, and microenvironmental barriers within the pancreas limiting CD8+ T cell priming by cDC1s. The candidate will address this hypothesis in the following two specific aims: (Aim 1) Define the contribution of tumor cell plasticity mediated by EMT-inducing transcription factors on acquired resistance to immunotherapy, and (Aim 2) Determine whether cDC1 dysfunction within the pancreatic microenvironment limits CD8+ T cell priming against highly antigenic tumors. Dr. Diamond has assembled a team of successful physician scientists at the University of Pennsylvania, including his primary mentor Dr. Robert Vonderheide, to serve as his advisory committee and oversee his research and career development. Dr. Diamond will also benefit from an excellent institutional environment that includes unique resources, mentorship, and a strong scientific community. The comprehensive career development plan and intensive research training outlined in this proposal will allow Dr. Diamond to acquire the necessary tools for an independent career as a physician scientist in oncology.