SR-A as a therapeutic target in breast cancer

ABSTRACT Tumor-associated macrophages are critical regulators of tumor development, progression, and metastasis. Factors in the tumor microenvironment induce tumor-associated macrophages to adopt a tumor-supportive phenotype that suppresses immune responses. The accumulation of tumor-supportive macrophages in tumors is associated with accelerated tumor progression and a poor patient prognosis. Macrophages sense and respond to their environment by expressing pattern-recognition receptors such as Class-A Scavenger Receptors (SR-A). In preliminary data, we show that SR-A binds to glycans expressed on breast cancer cells but not on non-cancer cells. Furthermore, we show that SR-A expression promotes the development of palpable tumors and lung metastases in mouse models that spontaneously develop breast cancer. Importantly, results from gene expression profiling indicate that tumor-associated macrophages adopt an immune-suppressive phenotype in SR-A-expressing mice but not in SR-A knock-out mice. These findings support the novel conclusion that SR-A binding to tumor-specific ligands induces the polarization of tumor-infiltrating macrophages toward an immune- suppressive phenotype that enhances breast cancer growth and metastases. It logically follows that inhibiting SR-A interactions in tumors may provide an innovative approach that repolarizes TAMs to an antitumor phenotype, improves the effectiveness of anti-tumor immune response, and inhibits breast cancer progression. Thus, the goals of the proposed experiments are to i) identify the ligands on breast cancer cells that bind SR-A and induce macrophage polarization toward a protumor phenotype, and ii) demonstrate that antagonizing SR-A repolarizes macrophages toward a tumor-inhibitory phenotype, enhances the immune response, and prolongs survival in preclinical models of breast cancer. Showing that antagonizing SR-A interactions increases anti-tumor immune activity and prolongs survival in animal models will confirm the therapeutic potential of this approach to treat breast cancer. In addition, identifying tumor-associated ligands that interact with SR-A may suggest additional tumor-specific strategies for inhibiting these interactions.