Dissection of the T cell infiltrate in mouse pancreatic tumors reveals an extensive and diverse tumor-reactive T cell repertoire

Although pancreatic cancer is generally refractory to immune checkpoint blockade, recent studies of tumor-infiltrating T cells in human tumor samples demonstrated the presence of in vivo expanded, tumor-reactive T cell receptor (TCR) clonotypes. Here, we explored the T cell repertoire in a murine pancreatic cancer model by combining single-cell transcriptomics with functional TCR characterization. This uncovered a substantial diversity of tumor-reactive TCR clonotypes. Whereas some of these were exclusively reactive against the autologous tumor, most TCRs reacted against syngeneic tumor cells of diverse tissue origin. Immunopeptidome analyses revealed three T cell epitopes reflecting distinct tumor antigen classes also found in human cancers: a mutanome-encoded neoantigen, an epitope encoded by an ectopically expressed endogenous retroviral provirus, and an epitope derived from a cell stress–induced autoantigen. These findings underline the importance of uncovering the antigen specificity of the natural tumor-reactive TCR repertoire to assess its therapeutic potential and safety with regard to personalized immunotherapy.