Macrophage Class A Scavenger Receptors Bind Tumor‐Associated Carbohydrate Antigens and Promote Breast Cancer Growth and Metastases in Mice

Abstract

Tumor‐associated macrophages (TAMs) play a key role in determining the immune response in cancer. Macrophages express pattern‐recognition receptors, such as Class A Scavenger Receptors (SR‐A), that bind a variety of different ligands and regulate macrophage immune phenotype. SR‐A expression by TAMs is thought to reflect a tumor‐promoting M2 macrophage phenotype, and the accumulation of SR‐A expressing macrophages is associated with increased tumor aggressiveness and poor patient prognosis in a variety of cancers, including breast cancer. Previous studies indicate that SR‐A ligands are present in the medium of cultured tumor cells. To test the possibility that SR‐A may directly bind to tumor cells, we developed a flow cytometry based binding assay using a soluble SR‐A (sSR‐A) protein and showed that SR‐A binds directly to breast cancer cells. This binding depended on glycosylation indicating SR‐A binds to cell‐surface glycans on tumor cells, which is important because tumor‐associated carbohydrate antigens (TACAs) are associated with immune suppression, tumor progression, and poor prognosis for breast cancer patients. The ability of SR‐A to bind TACAs was tested using carbohydrate mimetic peptides (CMPs) that are structurally similar to TACAs. sSR‐A bound to CMPs, and a CMP designed to react with mannose‐rich structures blocked sSR‐A binding to tumor cells. Because SR‐A induces an immune‐suppressive macrophage phenotype, we hypothesized that SR‐A would enhance the progression of breast cancer. Using mouse models of spontaneous breast cancer, our results show that development of palpable tumors was significantly delayed and the number of lung metastases significantly decreased in mice that do not express SR‐A (SR‐A−/−). These findings demonstrate that SR‐A binds to TACAs on breast cancer cells, and that SR‐A enhances breast cancer growth and metastases. Together with previous findings, our results indicate a model in which SR‐A binds to TACAs to induce an immune‐suppressive macrophage phenotype, which contributes to immune suppression, tumor growth, and metastases.Support or Funding InformationThis research was supported by grants from the NIH (R21CA185691), the Arkansas Breast Cancer Research Program, and a DEAP award from UAMS.