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), that are pivotal in regulating macrophage activation and polarization to different phenotypes. While evidence links an increased prevalence of SR-A-expressing TAMs to worse patient outcomes in certain cancers, a definitive role for SR-A in cancer remains to be fully established. Using mouse models of spontaneous breast cancer, we found that the absence of SR-A expression significantly delayed the development of palpable tumors and decreased the number of lung metastases in tumor-bearing mice. Next, we utilized a soluble SR-A protein to demonstrate that SR-A binds specifically to glycans on the surface of breast cancer cells. We used single-cell RNA sequencing of isolated TAMs to understand how SR-A promotes breast cancer progression. We identified a distinct SR-A-dependent TAM subpopulation characterized by high arginase (Arg1) gene expression and low expression of MHCII and other immune response-related genes. The gene-expression profile and signaling-pathway activity of TAMs in this subpopulation indicate that SR-A induces a tumor-supportive TAM phenotype in the tumor microenvironment. Together, our findings demonstrate a specific role for SR-A in binding to glycans on breast cancer cells, inducing a tumor-supportive TAM phenotype, and promoting breast cancer progression. These results shed light on the complex interplay between TAMs and cancer cells, and provide new insights into potential targets for therapeutic intervention in breast cancer. Overall design: To determine if SR-A is involved in the progression of breast cancer, we compared tumor growth and metastasis in PyMT-SR-A-/- mice with their wild-type control counterparts (PyMT-SR-A+/+)