Expanding the antigen repertoire in pancreatic cancer 4599

Abstract Description Immune checkpoint blockade therapy is ineffective in treating pancreatic ductal adenocarcinoma (PDAC), a tumor that is characterized by an immunosuppressive microenvironment and poor CD8+ T cell infiltration. However, recent clinical trials that vaccinate against neoantigens expressed in resected PDAC tumors have demonstrated efficacy in preventing recurrence of disease. Despite therapeutic success in a subset of patients, PDAC harbors a low mutational burden and express limited to undetectable neoantigens as defined by mutated peptides. Here we investigate whether other sources of antigen, such as non-canonical translation events, are presented by PDAC cells and can serve as vaccination targets. Using an oncogenic KrasG12D/+ ; p53-/- mouse model of PDAC, we examine translation patterns via ribosomal profiling and antigen presentation via mass spectrometry. Inducible affinity tags in endogenous MHC-I and ribosomal protein alleles enable cancer cell specific immunopeptidomics and Ribo-seq. Beyond exploring antigen presentation in transformed versus healthy cells, we seek to understand the role of cancer treatments in altering the immunopeptidome. The Kras inhibitor, MRTX1133, results in tumor regression but not clearance of PDAC. Considering minimal residual disease contains an infiltration of CD8+ T cells, we define antigens present after Kras inhibition and whether combination therapy with vaccination enhances survival in preclinical models. Funding Sources Lustgarten Foundation for Pancreatic Cancer Research, Koch Institute Frontier Research Award, Damon Runyon Cancer Research Foundation, NCI Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)