Targeting RAGE-mediated immunosuppression to enhance radiotherapy efficacy in glioblastoma 3169

Abstract Description Glioblastoma (GBM) is the most common malignant primary brain tumor. Severe and prolonged lymphopenia can occur in GBM patients after chemoradiotherapy. We found that radiation therapy (RT) increased myeloid-derived suppressor cells (MDSCs) and enhanced receptors for advanced glycation end products (RAGE) ligands such as S100A8/9 and HMGB1. We hypothesized that targeting RAGE receptors would prevent immunosuppression in preclinical GBM models. To test our hypothesis, we employed a syngeneic orthotopic GBM mouse model using C57BL/6 mice implanted with GL261 or CT2A cells. We treated the mice with five doses of 2 Gy/day for 5 consecutive days, combined with the RAGE inhibitor (RAGEi). The survival was monitored in these treated mice for up to 60 days. We found that RT increased the plasma levels of HMGB1 and S100A8/A9 and G-MDSCs, M-MDSCs, and tumor-associated macrophages (TAMs), while reducing circulating T cells in both tumor models. Targeting RAGE receptors significantly improved survival in GBM mice, reduced circulating G-MDSCs and M-MDSCs, and restored T cells. Using RAGEi also reduced the infiltration of G-MDSCs, M-MDSCs, and TAMs in the tumor microenvironment while enhancing the infiltration of total CD8, activated CD8, and IFNγ+CD8 T cells and decreasing regulatory T cell infiltration. Our study demonstrates that targeting RAGE receptors in combination with RT effectively mitigated MDSC-mediated immunosuppression, restored T cell populations, and improved survival. Funding Sources Cantex Pharmaceuticals LLC, Delaware, USA Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)