Treg cells promote immunotherapy-induced immune evasion by restraining CD4 T cell control of MHC-I-deficient metastatic pancreatic cancer

  • Sci Immunol. 2026 Jun 26;11(120):eadz4302. doi: 10.1126/sciimmunol.adz4302.
Zoe C Schmiechen  1  2 ,  Eduardo Cruz-Hinojoza  1  2 ,  Audrey L Hilk  1  2 ,  Madeline A Ellefson  1  2 ,  Alexander K Tsai  1  2 ,  Olivia M Dres  3 ,  Liang-I Kang  4 ,  Michael J Geuenich  5  6 ,  Jonah Z Butler  1  2 ,  Adam L Burrack  1  2 ,  Brandon M Larsen  1  2 ,  Grant H Hickok  1  2 ,  Ebony A Miller  1  2 ,  Cara-Lin Lonetree  1  2 ,  Amrit Gaire  7  8 ,  Rachana Pandey  7  8 ,  Hezkiel A Nanda  7  8 ,  Indrajit Chaudhury  9 ,  Thomas Corbiere  9 ,  Thamotharampillai Dileepan  1  2 ,  Steven S Shen  7  8 ,  Kieran R Campbell  5  10  11  12 ,  David G DeNardo  3 ,  Ingunn M Stromnes  1  2  13
Affiliations
  • 1. Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA.
  • 2. Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA.
  • 3. Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • 4. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
  • 5. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
  • 6. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 7. Institute for Health Informatics, University of Minnesota Medical School, Minneapolis, MN, USA.
  • 8. Clinical Translational Science Institute, University of Minnesota Medical School, Minneapolis, MN, USA.
  • 9. Caris Life Sciences, Phoenix, AZ, USA.
  • 10. Division of Oncology, Department of Statistical Sciences, University of Toronto, Toronto, ON, Canada.
  • 11. Ontario Institute for Cancer Research, Toronto, ON, Canada.
  • 12. Vector Institute, Toronto, ON, Canada.
  • 13. Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN, USA.
PMID: 42361199 DOI: 10.1126/sciimmunol.adz4302
Abstract

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 (Treg 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, Treg 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.

Products