Abstract B024: Contributions of tumor associated macrophage-mediated efferocytosis to breast cancer progression

Abstract Tumor cell apoptosis is a frequent and ongoing event during cancer initiation and progression with complex consequences for neighboring tumor cells and the tumor microenvironment. While apoptosis can serve to eliminate damaged or unfit cells, the downstream effects of cell death can actively modulate the tumor microenvironment in ways that promote malignancy. In particular, the clearance of apoptotic tumor cells, termed efferocytosis, by tumor associated macrophages has been implicated in contributing to an immunosuppressive tumor microenvironment and facilitating tumor progression. While recent studies have highlighted the heterogeneity of tumor associated macrophage phenotype and function in the tumor microenvironment, less is known regarding the specific phenotypic subsets of macrophages involved in the clearance of apoptotic tumor cell debris. We have found that a deletion of a specific phenotypic subset of macrophages that expresses high levels of the cell surface marker lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) is associated with an accumulation of apoptotic cells within the tumors, suggesting a role for these macrophages in apoptotic cell clearance. In further studies, using both in vitro models of LYVE-1 macrophages and in vivo mouse mammary tumor models, we have found that LYVE-1-expressing macrophages are more effective at clearing apoptotic cells compared with macrophages that do not express LYVE-1. Furthermore, we demonstrate that apoptotic cell clearance by LYVE-1 macrophages is partially dependent on Mer proto-oncogene tyrosine kinase (MerTK) activity. To define how apoptotic cell clearance alters the tumor microenvironment, we exposed LYVE-1 macrophages to apoptotic debris and found that these macrophages produce soluble factors, including complement component 1q (C1q), that drive fibroblast migration and activation. These findings provide a direct link between LYVE-1 macrophage-mediated efferocytosis and tissue remodeling. To define the niche associated with LYVE-1 macrophages in human breast cancer, we performed spatial transcriptomics on a panel of human breast cancer samples and found that a gene signature associated with LYVE-1 macrophage function is enriched in areas associated within the stromal compartment of the invasive margin of human breast cancer samples. This niche was found to be independent of breast cancer subtype. Further pathway analysis demonstrates that this gene signature is associated with tissue remodeling, complement, and regulation of inflammation. Finally, analysis of TCGA data reveals that increased levels of this gene signature are associated with reduced overall survival of breast cancer patients. These findings support a key role for LYVE-1 macrophages in clearance of apoptotic tumor debris, tissue remodeling, and promoting breast cancer progression. Citation Format: Kathryn L. Schwertfeger, Alexis K. Elsftrum, Yuyu He, Christine O'Connor, Lyndsay E. Reese, Madison Cocker, Brenna N. Walton, Andrew C. Nelson. Contributions of tumor associated macrophage-mediated efferocytosis to breast cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B024.