Abstract A086: Myeloid suppression within metastatic tumor microenvironments in advanced breast cancer—friend or foe to checkpoint inhibition?

Abstract Liver and lung metastases are major drivers of breast cancer-related morbidity, characterized by poor therapeutic outcomes and diminished overall survival. These dynamic tumor microenvironments (TMEs) display distinct, site-specific cellular architectures, including cytotoxic lymphocytes, immune suppressor cells, and stromal components, which together facilitate tumor growth and metastatic spread. Varied responses to immune checkpoint inhibition have also been observed in patients with differential tumor burden, improved responses in those with higher lung metastatic burden and poor responses in those with higher liver metastatic burden. Specific immune populations driving observed differential responses have not been fully characterized. Utilizing syngeneic orthotopic mouse models and FFPE tissue samples from patients with primary and metastatic breast cancer, we investigated the organ-specific cellular composition, cell-cell interactions, and molecular pathways underlying tumor progression, immune escape, and site-specific metastasis. Flow cytometry analysis of orthotopic murine primary breast, breast-to-liver, and breast-to-lung tumors demonstrated that CD3+ lymphocytes initially accumulate in primary tumors soon after tumor inoculation and decline significantly over time. Despite this overall lymphocyte depletion within TMEs, the lungs consistently exhibit the highest lymphocyte levels. In contrast, myeloid-derived suppressor cells (MDSCs) progressively infiltrate both primary and distant sites, exerting immunosuppressive functions that likely promote tumor progression and inhibit immune responses. Both granulocytic and monocytic MDSCs suppress CD8+ T cell proliferation through distinct organ-specific mechanisms, with the strongest suppressive effects observed in the liver TME. Validation of these findings in patient specimens using high-resolution spatial transcriptomics from breast and distant breast metastases using 10X Genomics (Visium and Visium-HD platforms) revealed that liver metastases harbor lower immune-to-stromal ratio with greater MDSCs: CD8+ colocalization, and higher expression of genes associated with proliferation, angiogenesis, anti-apoptosis and antiinflammation relative to primary breast tumors. In addition, spatiotemporal plasticity of breast TMEs is specific to the disease site, and investigation of how these observations could impact tumor progression and response to immune checkpoint inhibition is underway. In summary, tissue-specific programming of MDSCs in breast-to-liver metastasis compared with primary and breast-to-lung lesions leads to reduced T cell infiltration and function, and could contribute to a lack of response to checkpoint inhibition and could guide therapeutic options for patients. Citation Format: Batul Al-zubeidy, Edgar Gonzalez, Aaron Baugh, Dominic Zavala, Mathew Jacobo, Michael Press, Evanthia Roussos Torres. Myeloid suppression within metastatic tumor microenvironments in advanced breast cancer—friend or foe to checkpoint inhibition? [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A086.