Progesterone receptor-dependent downregulation of MHC class I promotes tumor immune evasion and growth in breast cancer
In vitro, we show that PR/progesterone signaling reduces APP gene expression and MHC class I expression in human and breast mammary tumor cell lines. PR-mediated attenuation of APP/MHC Class I expression is more pronounced in the presence of IFN. In immune cell killing assays, PR-expressing mammary tumor cells treated with progesterone are protected from immune-mediated cytotoxicity. We demonstrate that PR expression in vivo prevents immune-mediated rejection of xenoantigen-modified mammary tumor cell lines through mechanisms involving MHC Class I expression and CD8 T cells. Data analysis of two large BC cohorts reveals lower APP gene expression and MHC Class I expression in ER/PR-positive tumors compared with ER-positive/PR-negative tumors. These findings show that HR+BCs, specifically PR+tumors, downregulate APP/MHC class I machinery through PR/progesterone signaling. Use of pharmacological PR/progesterone inhibitors may reverse these effects in patients with BC, thereby improving immunosurveillance and response to immunotherapies.
Authors
- Jun-Ping Wei (ORCID: https://orcid.org/0000-0001-6311-6033)
- Hisham Mohammed (ORCID: https://orcid.org/0000-0003-0275-9793)
- Jeffery M. Vahrenkamp (ORCID: https://orcid.org/0000-0002-2937-1513)
- Gangjun Lei (ORCID: https://orcid.org/0000-0002-0505-0475)
- Eilidh I Chowanec (ORCID: https://orcid.org/0000-0002-3319-0256)
- Xiaopeng Sun (ORCID: https://orcid.org/0009-0009-5219-8964)
- Mary A. Markiewicz (ORCID: https://orcid.org/0000-0001-5685-8573)
- Amanda Heard (ORCID: https://orcid.org/0000-0002-7150-7998)
- Jason Gertz (ORCID: https://orcid.org/0000-0001-7568-6789)
- Cong-Xiao Liu
- Lauryn R. Werner (ORCID: https://orcid.org/0000-0003-3876-2556)
- Zachary C. Hartman (ORCID: https://orcid.org/0000-0001-6549-8207)
- Charles M. Perou (ORCID: https://orcid.org/0000-0001-9827-2247)
- Melissa A. Troester (ORCID: https://orcid.org/0000-0001-9506-6624)
- Andrea Wilson (ORCID: https://orcid.org/0000-0002-9773-6975)
- Harmony Saunders
- Christy R. Hagan (ORCID: https://orcid.org/0000-0003-2524-1815)
- Justin Micah Balko (ORCID: https://orcid.org/0000-0002-4263-5974)
- Prabhakar Chalise (ORCID: https://orcid.org/0000-0001-5581-1220)
- Julio C Tinoco (ORCID: https://orcid.org/0000-0001-9182-8695)
- Hugo Cros
Institutions
- University of North Carolina at Chapel Hill (US)
- Oregon Health & Science University (US)
- Duke University (US)
- University of Utah (US)
- The University of Kansas Cancer Center (US)
- University of Kansas Medical Center (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Journal for ImmunoTherapy of Cancer
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1136/jitc-2024-010179
- Citations
- 4
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 3.19
Funders
- U.S. Department of Defense
- Breast Cancer Alliance
- Susan G. Komen
- National Institutes of Health
- School of Medicine, University of Kansas
- National Cancer Institute
- National Institute of General Medical Sciences