{
  "abstract": "Background: Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with limited therapeutic options. Adoptive cell therapy (ACT) using tumor-reactive T cell receptor-engineered T cells (TCR-T) is a promising therapeutic modality for targeting PDA. However, additional strategies are needed to overcome the suppressive tumor microenvironment (TME) that impairs T cell persistence and function. Tumor growth factor-β (TGFβ) is a prominent immunosuppressive component of the TME, but is also believed to be critical for T cell memory.\n\nMethods: We develop aggressive immunocompetent orthotopic KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) PDA mouse models to identify obstacles to sustained activity of TCR-T cell therapy targeting the native tumor antigen, mesothelin (Msln). During ACT, we track TCR-T cell fate, function, antitumor effects, and interactions with type I dendritic cells using flow cytometry, two-photon microscopy, and live-cell imaging. Based on an abundance of TGFβ and a halt in TCR-T cell differentiation in orthotopic tumors, TCR-T cells with defective Tgfbr2 are tested in a new model, where peptide-major histocompatibility complex-I (pMHC-I) is incrementally augmented on KPC tumor cells.\n\nResults: TCR-T cells accumulated in orthotopic PDA but were rendered dysfunctional despite lacking features of exhaustion. KPC tumor cells express minimal constitutive MHC-I, resulting in suboptimal recognition by TCR-T cells. Modestly increasing pMHC-I on KPC tumor cells restored canonical differentiation of TCR-T cells into PD-1+ progenitor exhausted (TPEX) in PDA, but failed to rescue interferon-γ (IFNγ) production. TGFβ was enriched in tumor nests, and deletion of Tgfbr2 in TCR-T cells enhanced dendritic cell interactions, reduced intratumoral TGFβ deposition, restored IFNγ production, and improved therapeutic efficacy without compromising TCR-T cell longevity or tissue residency.\n\nConclusions: Modestly enhancing tumor-intrinsic pMHC-I unleashes therapeutic efficacy and functionality of Tgfbr2-disrupted TCR-T cells in PDA.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA",
    "Center for Immunology, University of Minnesota, Minneapolis, Minnesota, USA",
    "Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA",
    "Program in Immunology and Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA",
    "Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA",
    "Center for Multiparametric Imaging of Tumor Immune Microenvironments, University of Minnesota, Minneapolis, Minnesota, USA",
    "Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA",
    "Pancreatic Cancer Center of Excellence, University of Nebraska Medical Center, Omaha, Nebraska, USA",
    "Departments of Immunology and Medicine/Oncology, University of Washington, Seattle, Washington, USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 20,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Alexander K Tsai",
      "orcid": "0000-0002-4014-1946"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Meagan R Rollins"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Madeline A Ellefson"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Zoe C Schmiechen"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Adam L Burrack"
    },
    {
      "affs": [
        3
      ],
      "name": "Ayaka Hulbert"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Guhan Qian"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Hongrong Zhang"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Eduardo Cruz-Hinojoza"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Jonah Z Butler"
    },
    {
      "affs": [
        1
      ],
      "name": "Jason S Mitchell"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Olivia C Ghirardelli Smith"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Stephen D O’Flanagan"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Jenny Krause"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Grant H Hickok"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Paolo P Provenzano"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "David Masopust"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Sunil R Hingorani"
    },
    {
      "affs": [
        3,
        8
      ],
      "name": "Philip D Greenberg"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Ingunn M Stromnes",
      "orcid": "0000-0001-8120-4547"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9exgdgxfbpzrc.bib",
  "cited_by": 1,
  "doi": "10.1136/jitc-2026-015489",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13723925/",
  "id": "9exgdgxfbpzrc",
  "issns": [
    "2051-1426"
  ],
  "landing_url": "https://doi.org/10.1136/jitc-2026-015489",
  "language": "en",
  "licence": "CC-BY-NC-4.0",
  "licence_label": "CC BY-NC 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "1506"
    ],
    [
      "heading",
      "2436"
    ],
    [
      "heading",
      "Immune Cell Therapies and Immune Cell Engineering"
    ],
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2730|CAR-T cell therapy research"
    ]
  ],
  "openalex": "W4411130738",
  "pdf_url": "https://jitc.bmj.com/content/14/10/e015489.full.pdf",
  "pmcid": "PMC13723925",
  "pmid": "42957343",
  "published": "2026-10-29",
  "publisher": "BMJ Publishing Group",
  "ris": "https://research.draconitic.com/paper/9exgdgxfbpzrc.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T12:22:28Z",
      "native_id": "PMC13723925",
      "source": "pmc",
      "url": "https://doi.org/10.1136/jitc-2026-015489"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|CAR-T cell therapy research",
      "subfield": "oncology"
    }
  ],
  "title": "Promoting tumor antigen presentation unleashes therapeutic efficacy of Tgfbr2-deficient TCR-engineered T cells in pancreatic ductal adenocarcinoma",
  "title_text": "Promoting tumor antigen presentation unleashes therapeutic efficacy of Tgfbr2-deficient TCR-engineered T cells in pancreatic ductal adenocarcinoma",
  "type": "peer-reviewed",
  "updated_at": "2026-11-05T12:20:39Z",
  "url": "https://research.draconitic.com/paper/9exgdgxfbpzrc",
  "venue": "Journal for Immunotherapy of Cancer",
  "versions": []
}