Abstract 6165: Antiprogestin- mediated endocrine therapy activates immunotherapy- responsive programs in hormone receptor positive breast tumors

Abstract The endocrine status of the patient is a critical factor that may modulate the immune response in breast cancer and, accordingly, should be considered during immunotherapy regimens. Given the immunosuppressive and tolerogenic activities of the sexual hormone progesterone and its roles in promoting breast cancer initiation, we aim to evaluate the effect of the antagonist of the classical progesterone receptor, Mifepristone (MIFE), as an endocrine therapy to alter the tumor microenvironment, and particularly to shape an immunogenic and immunotherapy-responsive profile. We evaluated the breast tumor immune landscape both in a mouse model of luminal tumors (C4HD) treated with a synthetic progestin MPA and with MIFE; and in human tumor samples derived from the MIPRA clinical trial (NCT02651844), where breast cancer patients harbouring HR+ tumors were treated with MFP for 14 days before surgery. Using RNA-seq, bioinformatics tools and flow cytometry, we interrogated the C4HD tumor immune infiltration profile after MPA and MIFE treatment, including several global gene expression signatures associated with T-cell exclusion and Immune Checkpoint Inhibitors (ICI) sensitivity and resistance. We observed that treatment with MFP in HR+ luminal breast tumors restrains the progestin-mediated tolerogenic infiltrate composed of Tregs, exhausted CD8+ T cells and TAM macrophages. Importantly, MIFE downregulates the suppressive pathway of IDO, CXCL5, VEGF and Galectin-9, which in turn contributes to the persistence of a population of CD8+ T cells that highly produce granzymes and express lower TIM-3 and PD-1, exhibiting a reinvigorating phenotype. On the contrary, MIFE treatment upregulated several immune-associated genes such as chemokines, granzymes, ICOS-L, EOMES, CD86, CD8 and PD-L1. More importantly, we showed that in both mouse models and human tumors, treatment with MIFE reverts transcriptional signatures associated with T cell exclusion and ICI resistance and significantly upregulates programs associated with immunogenic cell death and PD-1/PD-L1 treatment response. To summarize, our results demonstrate that endocrine therapy as MIFE can foster in HR+ tumors a complete remodelling of the immune landscape, promoting immune cell infiltration and immunogenicity. As a result of the neoadjuvant MIFE treatment, HR+ luminal tumors that traditionally were considered “cold” tumors are now heavily enriched with an immunogenic PD-L1-expressing infiltrate, thus opening a new window of treatment opportunity that may sensitize luminal breast tumors to ICI. Citation Format: Mariana Salatino, Joaquin Pedro Merlo, Tomas Dalotto-Moreno, Magalí Bertón, Ramiro Martin Perrotta, Andres Elia, Karina V. Mariño, Claudia M. Lanari, Gabriel A. Rabinovich. Antiprogestin- mediated endocrine therapy activates immunotherapy- responsive programs in hormone receptor positive breast tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6165.