Expression of a neoantigen renders pancreas cancer transiently susceptible to immunotherapy

Abstract

Abstract Immune checkpoint blockade has been largely ineffective for treating pancreatic ductal adenocarcinoma (PDA). Here, we develop a novel model of pancreatic cancer to investigate reasons for response and failure to immune checkpoint blockade in this lethal malignancy. Primary tumor epithelial cell clones from the genetically engineered KPC mouse model transduced to express a specific luciferase antigen, commonly used for bioluminescent in mice, rapidly establish tumors similar to parental cells after orthotopic implantation into syngeneic mice. Unexpectedly, αPD-L1 or αPD-1, which fail to elicit responses to luciferase- KPC parental cells, induce objective responses to luciferase+ KPC clones and prolong animal survival. We identify the immunodominant luciferase H- 2Db-restricted epitope and generate a fluorescently labeled peptide:MHC tetramer that specifically binds PDA-specific CD8 T cells. Up to 40% of tumor-infiltrating T cells bind this tetramer, yet most of these cells co-express PD-1 and Lag-3 and are dysfunctional. αPD-L1 enhances the systemic expansion of tetramer+ T cells and induced the accumulation of PD-1+ Ki67+ and Ki67- tetramer+ T cells in PDA. αPD-L1 significantly reduced the frequency of intra-tumoral tetramer+ T cells that expressed Lag-3 resulting in enhanced ex vivo peptide-specific cytokine production. However, tumors rapidly returned despite T cell infiltration and prolonged immunotherapy. Current efforts are underway to study the evolution of PDA-specific T cells and tumor clones using single cell technologies to inform clinical immunotherapy design.