Dissection of the T cell infiltrate in mouse pancreatic tumors reveals an extensive and diverse tumor-reactive T cell repertoire
- Hannes Kehm
- Stefan Zens
- Daniel Baumann
- Zibo Meng
- Arnoud H. de Ru
- Rayman T. N. Tjokrodirijo
- Caroline Vent
- Olga Murawjew
- Sarah Braun
- Anne Weiss
- Florian Bieberich
- Aline Konrad
- Francesca Lucato
- Janne Kühner
- Sonia Gutierrez Minguez
- Chin Leng Tan
- Jonas D. Förster
- Mogjiborahman Salek
- Angelika B. Riemer
- Michael Volkmar
- Peter van Veelen
- Isabel Poschke
- Rienk Offringa
2026-04-10
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.