Abstract 3972: The role of myeloid derived suppressor cells in organ-specific breast cancer metastasis

The liver and lungs are the most common sites of breast cancer metastasis, associated with poor prognosis and limited response to systemic therapies. These tumor microenvironments (TMEs) exhibit distinct cellular compositions and molecular mechanisms that promote tumor growth and metastatic progression. Visceral organs differentially recruit specific immune populations that foster protumor interactions, contributing to the poor therapeutic response to immunotherapy. To explore the role of TMEs in tumor progression, immune evasion, and metastasis, we employed an orthotopic mouse model inoculated with an ERBB2/HER2-enriched breast cancer cell line. Flow cytometry analysis of primary breast tumor, and liver and lung metastases showed an early accumulation of CD3+ lymphocytes in primary tumors shortly after inoculation, which significantly declined over time. Despite this overall reduction in lymphocytes within tumor microenvironments (TMEs), the lungs consistently maintained the highest levels of lymphocyte infiltration. Conversely, myeloid-derived suppressor cells (MDSCs) progressively infiltrated both primary and metastatic sites, exerting potent immunosuppressive effects that likely facilitate tumor progression and dampen immune responses. MDSCs derived from liver and lung metastases, but not from the primary tumor, suppressed CD8+ T cell proliferation and significantly inhibited the production of cytotoxic cytokines, such as granzyme A. The most pronounced suppression was observed in breast-to-liver metastases. Flow cytometry analysis revealed that MDSC-mediated immunosuppression varies by microenvironment, with predominant arginase release in the liver, inducible nitric oxide synthase (iNOS) production in the lung, and interleukin-10 secretion in the primary tumor. Additionally, in the liver TME, CD11b+ F4/80+ tumor-associated macrophages (TAMs) exhibited higher arginase activity than MDSCs, further enhancing the suppressive microenvironment. These immunosuppressive cytokines likely impair the function of tumor-infiltrating lymphocytes (TILs) within their respective TMEs, highlighting the need to investigate organ-specific mechanisms of immunosuppression. Notably, liver metastases harbor the lowest levels of antitumor lymphocytes and the highest suppressive MDSC activity compared to lung metastases and the primary tumor. These immune alterations are likely initiated shortly after tumor seeding, emphasizing the importance of early intervention in metastatic disease. In summary, the tissue-specific programming of MDSCs in breast-to-liver metastases, compared to primary tumors and breast-to-lung lesions, results in reduced T cell infiltration and impaired T cell function. These findings underscore the importance of developing niche-specific immunotherapeutic strategies to address organ-specific immune suppression. Citation Format: Batul Al-zubeidy, Edgar Gonzalez, Aaron Baugh, Matt Jacobo, Evanthia Roussos Torres. The role of myeloid derived suppressor cells in organ-specific breast cancer metastasis [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 3972.