Class A scavenger receptors promote tumor progression and induce a unique macrophage phenotype in a mouse model of spontaneous breast cancer

Tumor-associated macrophages (TAMs) are a critical component of the immune response to cancer, and their role in modulating cancer progression is well-recognized. Macrophages express pattern-recognition receptors, including Class A scavenger receptors (SR-A), which are pivotal in regulating macrophage activation and polarization into distinct phenotypes. SR-A expression is generally correlated with altered cytokine expression indicative of a tumor-supportive M2 macrophage phenotype. While evidence links an increased prevalence of SR-A-expressing TAMs to worse patient outcomes in breast cancer, a definitive role for SR-A and its potential ligands in cancer remains to be fully established. We previously reported that the fibroblast-activated proteinase (FAP)-cleaved collagen is a ligand for SR-A. This study was conducted to assess the role of FAP and SR-A expression in breast cancer. Using mouse models of spontaneous breast cancer, we found that the absence of SR-A, but not FAP, expression significantly delayed the development of palpable tumors and decreased the number of lung metastases in tumor-bearing mice. A soluble SR-A protein was used to demonstrate that SR-A binds to glycans on the surface of breast cancer cells. We used single-cell RNA sequencing and flow cytometry of isolated TAMs and identified a distinct SR-A-dependent TAM subpopulation characterized by high arginase 1 gene expression. Pathway analysis of TAMs associates SR-A expression with activation of transcriptional programs linked to immune-suppressive macrophage phenotypes. These results define a contributory role for SR-A in breast cancer progression and provide new insights into the complex interactions between TAMs and cancer cells in the tumor microenvironment.