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Immunol."],"published-print":{"date-parts":[[2026,6,26]]},"abstract":"<jats:p>\n                    Mechanisms driving immunotherapy resistance in pancreatic cancer are poorly defined. We demonstrate that programmed death-ligand 1 immune checkpoint blockade promoted immune evasion by epigenetic\n                    <jats:italic toggle=\"yes\">Tap1<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">transporter associated with antigen processing 1<\/jats:italic>\n                    ) silencing, increasing selection of metastatic tumor variants with defective interferon-\u03b3 (IFN-\u03b3)\u2013inducible class I major histocompatibility complex (MHC-I) expression. Unleashing CD4 conventional T cells by regulatory T cell (T\n                    <jats:sub>reg<\/jats:sub>\n                    cell) depletion, transfer of tumor-reactive CD4 T cells, or anti\u2013CTLA-4 prevented metastasis. Tumor-specific CD4 T cells adopted a TCF-1\n                    <jats:sup>+<\/jats:sup>\n                    SLAMF6\n                    <jats:sup>+<\/jats:sup>\n                    progenitor state in lymph nodes and differentiated in tumors. Anti\u2013CTLA-4 increased intratumoral accumulation of CD4 T cells with stemness and tissue residency features, reduced metastasis, and induced gene signatures correlated with improved patient outcomes. MHC-I restoration with anti\u2013CTLA-4 prolonged survival in murine models. In patient tumors, T\n                    <jats:sub>reg<\/jats:sub>\n                    cells and CD4 T cells colocalized, and abundance correlated with survival. These findings identify targetable mechanisms of immune evasion and metastasis in immunotherapy-resistant cancer.\n                  <\/jats:p>","DOI":"10.1126\/sciimmunol.adz4302","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T17:58:47Z","timestamp":1782496727000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["T\n                    <sub>reg<\/sub>\n                    cells promote immunotherapy-induced immune evasion by restraining CD4 T cell control of MHC-I\u2013deficient metastatic pancreatic cancer"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3403-6824","authenticated-orcid":true,"given":"Zoe C.","family":"Schmiechen","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA."},{"name":"Center for Immunology, University of Minnesota Medical 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