Adenosine Suppresses Microglial Immunity in Breast Cancer Brain Metastasis 2306834

Abstract

Abstract Introduction Breast cancer brain metastasis (BCBM) is a fatal and increasingly common complication in breast cancer patients. The blood—brain barrier (BBB) limits the efficacy of many conventional therapies, contributing to poor prognosis. Immune cells, however, can cross the BBB, making immunotherapy a promising treatment strategy. Microglia, the brain’s resident macrophages, are first responders in central nervous system diseases and can eliminate cancer cells via phagocytosis. Microglia are part of a larger immune microenvironment and interact with various other immune cells, including regulatory T cells (Tregs). Tregs normally maintain self-tolerance, but can also suppress anti-tumor immunity. However, the interaction between Tregs and microglia during BCBM remains poorly understood. Preliminary analyses highlight an adenosine-mediated signaling axis, suggesting a mechanism by which Tregs may inhibit microglial function. We hypothesize that Treg-derived adenosine, produced via CD73, suppresses microglial anti-tumor activity by signaling through the adenosine A3 receptor (A3AR) on microglia. Methods Here, we employ a combination of in vitro and in vivo studies. In vitro, microglia were treated with lipopolysaccharide and adenosine, and activation was assessed by flow cytometry. In vivo, we modeled BCBM using intracranial injection of E0771 breast cancer cells in mice, treated animals with a CD73-blocking antibody, and analyzed immune responses by flow cytometry. Results In vitro, we demonstrated that treatment of microglia with soluble adenosine reduced microglial activation. Treatment of mice bearing BCBM with a CD73 blocking antibody lead to a moderate decrease in tumor burden, expansion of T cells, and increased microglial antigen presentation. Conclusion These findings support that Treg CD73-derived adenosine may contribute to BCBM immunosuppression through A3AR signaling in microglia. Funding Source NIH T34GM136498 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)