ArticleJournal for immunotherapy of cancer2025
Progesterone receptor-dependent downregulation of MHC class I promotes tumor immune evasion and growth in breast cancer.
Article in Journal for immunotherapy of cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- The immunology of human breast cancer.Nature reviews. Immunology · 2026Review
- Breast cancer immunogenicity as a spectrum: evolving concepts and therapeutic implications.The Journal of clinical investigation · 2026Review
- From State, Pathway, to Niche: The Ternary Network of Breast Cancer Stem-like Cells Driving Tumor Progression and Combination Therapy Prospects.Biomolecules · 2026Review
- Grade III canine and feline mammary carcinomas are associated with an immunosuppressed, vascularized and proliferative microenvironment.BMC veterinary research · 2026Article
- Sex Differences in Cancer Immunotherapy-Clinical Evidence and Mechanisms With a Focus on NSCLC.Immunological reviews · 2026Review
- Integrative multi-omics analysis identifies SNRPE as a key driver gene in uterine corpus endometrial carcinoma: promoting tumor progression, and mediating immune evasion.Frontiers in immunology · 2026Article
- Immune evasion driven by lipid metabolic reprogramming in endocrine-resistant HRFrontiers in immunology · 2026Review
- [Research Advances on the Immune Evasion Mechanisms of Disseminated Tumor Cells and Their Roles in Cancer Metastasis].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2025Review
- Toxic Epidermal Necrolysis and Steven-Johnson Syndrome During the Postpartum Period: A Literature Review with a Rare Case Presentation.Journal of clinical medicine · 2025Review
- Elevating MHC I expression on tumor cells by nanovesicles loading tyrosine kinase inhibitors can improve the efficacy of cancer vaccines.Frontiers in immunology · 2025Article
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Authors and funding
21 authors.
Funding
Abstract
backgroundBreast cancer (BC) continues to be a major health concern with 250,000 new cases diagnosed annually in the USA, 75% of which are hormone receptor positive (HR+), expressing estrogen receptor alpha (ER) and/or the progesterone receptor (PR). Although ER-targeted therapies are available, 30% of patients will develop resistance, underscoring the need for new non-ER/estrogen-based treatments. Notably, HR+BCs exhibit poor lymphocyte infiltration and contain an immunosuppressive microenvironment, which contributes to the limited efficacy of immunotherapies in HR+BC. In this study, we demonstrate that PR/progesterone signaling reduces major histocompatibility complex (MHC) Class I expression, facilitating immune evasion and escape from immune-based clearance of PR+tumors.
methodsTo determine the effect of PR/progesterone on MHC Class I expression, we treated human and mouse mammary tumor cell lines with progesterone and/or interferon (IFN) and measured expression of genes involved in antigen processing and presentation (APP), as well as surface MHC Class I expression. We used the OT-I/SIINFEKL model antigen system to measure the impact of progesterone on immune cell-mediated killing of modified tumor cells. We also analyzed two large BC clinical cohorts to determine how PR expression correlates with APP gene expression and MHC Class I expression in ER-positive tumors.
resultsIn 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.
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