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Adv."],"published-print":{"date-parts":[[2026,4,10]]},"abstract":"<jats:p>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\u2013induced 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.<\/jats:p>","DOI":"10.1126\/sciadv.adr6132","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T18:01:06Z","timestamp":1775844066000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["Dissection of the T cell infiltrate in mouse pancreatic tumors reveals an extensive and diverse tumor-reactive T cell repertoire"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1299-4754","authenticated-orcid":true,"given":"Hannes","family":"Kehm","sequence":"first","affiliation":[{"name":"Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg 69120, Germany."},{"name":"Faculty of Biosciences, Heidelberg University, Heidelberg 69120, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0538-9652","authenticated-orcid":true,"given":"Stefan","family":"Zens","sequence":"additional","affiliation":[{"name":"Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg 69120, Germany."},{"name":"Faculty of Biosciences, Heidelberg University, Heidelberg 69120, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4484-9973","authenticated-orcid":true,"given":"Daniel","family":"Baumann","sequence":"additional","affiliation":[{"name":"Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg 69120, Germany."},{"name":"Faculty of Biosciences, Heidelberg University, Heidelberg 69120, Germany."},{"name":"Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg 69120, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6690-7380","authenticated-orcid":true,"given":"Zibo","family":"Meng","sequence":"additional","affiliation":[{"name":"Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg 69120, Germany."},{"name":"Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg 69120, Germany."},{"name":"Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1166-4059","authenticated-orcid":true,"given":"Arnoud H.","family":"de Ru","sequence":"additional","affiliation":[{"name":"Center for Medical Systems Biology, Leiden University Medical Center, Leiden, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rayman T. 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