Promoting tumor antigen presentation unleashes therapeutic efficacy of Tgfbr2-deficient TCR-engineered T cells in pancreatic ductal adenocarcinoma
9 affiliations
- 1Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
- 2Center for Immunology, University of Minnesota, Minneapolis, Minnesota, USA
- 3Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA
- 4Program in Immunology and Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- 5Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA
- 6Center for Multiparametric Imaging of Tumor Immune Microenvironments, University of Minnesota, Minneapolis, Minnesota, USA
- 7Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
- 8Pancreatic Cancer Center of Excellence, University of Nebraska Medical Center, Omaha, Nebraska, USA
- 9Departments of Immunology and Medicine/Oncology, University of Washington, Seattle, Washington, USA
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.
Methods: 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.
Results: 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.
Conclusions: Modestly enhancing tumor-intrinsic pMHC-I unleashes therapeutic efficacy and functionality of Tgfbr2-disrupted TCR-T cells in PDA.
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BibTeX
@article{tsai2026promoting,
title = {{Promoting tumor antigen presentation unleashes therapeutic efficacy of Tgfbr2-deficient TCR-engineered T cells in pancreatic ductal adenocarcinoma}},
author = {Alexander K Tsai and Meagan R Rollins and Madeline A Ellefson and Zoe C Schmiechen and Adam L Burrack and Ayaka Hulbert and Guhan Qian and Hongrong Zhang and Eduardo Cruz-Hinojoza and Jonah Z Butler and Jason S Mitchell and Olivia C Ghirardelli Smith and Stephen D O’Flanagan and Jenny Krause and Grant H Hickok and Paolo P Provenzano and David Masopust and Sunil R Hingorani and Philip D Greenberg and Ingunn M Stromnes},
journal = {Journal for Immunotherapy of Cancer},
year = {2026},
month = oct,
doi = {10.1136/jitc-2026-015489},
url = {https://doi.org/10.1136/jitc-2026-015489},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Promoting tumor antigen presentation unleashes therapeutic efficacy of Tgfbr2-deficient TCR-engineered T cells in pancreatic ductal adenocarcinoma
AU - Alexander K Tsai
AU - Meagan R Rollins
AU - Madeline A Ellefson
AU - Zoe C Schmiechen
AU - Adam L Burrack
AU - Ayaka Hulbert
AU - Guhan Qian
AU - Hongrong Zhang
AU - Eduardo Cruz-Hinojoza
AU - Jonah Z Butler
AU - Jason S Mitchell
AU - Olivia C Ghirardelli Smith
AU - Stephen D O’Flanagan
AU - Jenny Krause
AU - Grant H Hickok
AU - Paolo P Provenzano
AU - David Masopust
AU - Sunil R Hingorani
AU - Philip D Greenberg
AU - Ingunn M Stromnes
PY - 2026
DA - 2026/10/29
JO - Journal for Immunotherapy of Cancer
DO - 10.1136/jitc-2026-015489
UR - https://doi.org/10.1136/jitc-2026-015489
AB - 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. Methods: 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. Results: 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. Conclusions: Modestly enhancing tumor-intrinsic pMHC-I unleashes therapeutic efficacy and functionality of Tgfbr2-disrupted TCR-T cells in PDA.
SN - 2051-1426
ER -