T <sub>reg</sub> cells promote immunotherapy-induced immune evasion by restraining CD4 T cell control of MHC-I–deficient metastatic pancreatic cancer
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 Tap1 ( transporter associated with antigen processing 1 ) silencing, increasing selection of metastatic tumor variants with defective interferon-γ (IFN-γ)–inducible class I major histocompatibility complex (MHC-I) expression. Unleashing CD4 conventional T cells by regulatory T cell (T reg cell) depletion, transfer of tumor-reactive CD4 T cells, or anti–CTLA-4 prevented metastasis. Tumor-specific CD4 T cells adopted a TCF-1 + SLAMF6 + progenitor state in lymph nodes and differentiated in tumors. Anti–CTLA-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–CTLA-4 prolonged survival in murine models. In patient tumors, T reg 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.
Authors
- Rachana Pandey (ORCID: https://orcid.org/0000-0001-8270-6725)
- Kieran R. Campbell (ORCID: https://orcid.org/0000-0003-1981-5763)
- Cara-lin Lonetree (ORCID: https://orcid.org/0000-0002-2760-8572)
- Adam L. Burrack (ORCID: https://orcid.org/0000-0002-4001-7849)
- Steven S. Shen (ORCID: https://orcid.org/0000-0001-7725-1260)
- Ingunn M. Stromnes (ORCID: https://orcid.org/0000-0001-8120-4547)
- Brandon M. Larsen (ORCID: https://orcid.org/0009-0003-5647-3202)
- Zoe C. Schmiechen (ORCID: https://orcid.org/0000-0002-3403-6824)
- Liang‐I Kang (ORCID: https://orcid.org/0000-0001-7025-3095)
- Alexander K. Tsai (ORCID: https://orcid.org/0000-0002-4014-1946)
- Ebony A. Miller
- David G. DeNardo (ORCID: https://orcid.org/0000-0002-3655-5783)
- Thamotharampillai Dileepan (ORCID: https://orcid.org/0000-0002-2810-6996)
- Amrit Gaire (ORCID: https://orcid.org/0000-0002-5655-9570)
- Indrajit Chaudhury (ORCID: https://orcid.org/0000-0003-3264-3177)
- Hezkiel A. Nanda (ORCID: https://orcid.org/0000-0003-1406-1659)
- Michael J. Geuenich (ORCID: https://orcid.org/0009-0001-8211-3070)
- Jonah Z. Butler (ORCID: https://orcid.org/0000-0002-8694-7590)
- Grant H. Hickok (ORCID: https://orcid.org/0009-0004-8235-4773)
- Audrey L. Hilk (ORCID: https://orcid.org/0009-0004-4402-8395)
- Eduardo Cruz-Hinojoza (ORCID: https://orcid.org/0000-0003-3279-133X)
- Madeline A. Ellefson
- Olivia M. Dres (ORCID: https://orcid.org/0000-0003-0310-0958)
- Thomas Corbiere
Institutions
- Ontario Institute for Cancer Research (CA)
- University of Minnesota (US)
- University of Toronto (CA)
- Washington University in St. Louis (US)
- Lunenfeld-Tanenbaum Research Institute (CA)
- Southern California Clinical and Translational Science Institute (US)
- Vector Institute (CA)
- Sinai Health System (CA)
- University of Minnesota Medical Center (US)
- Caris Life Sciences (United States) (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2026-06-26
- DOI
- https://doi.org/10.1126/sciimmunol.adz4302
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- American Cancer Society
- Pancreatic Cancer Action Network
- Princess Margaret Cancer Foundation
- National Institutes of Health
- Canadian Institutes of Health Research