Syst-32 a novel approach to target treg-mediated immunosuppression in gbm

Abstract Macrophage inflammatory protein-3, or MIP-3α, is a chemokine that is highly expressed in gliomas, with expression progressively increasing with tumor grade. It is one of the top expressed genes in pseudopalisading and perinecrotic zones of glioblastoma (GBM) and as a chemokine, can greatly influence tumor-immune interactions. The receptor for MIP-3α, CCR6, is found on a variety of GBM-infiltrating immune subsets such as γδ T cells, conventional CD4 T cells and most notably, Tregs, which is disproportionately increased in GBM patients. Patients with lower CCR6-MIP3α gene signatures in tumors have improved overall survival and disease-free progression. We have found that circulating MIP-3α is also increased in the presence of intracranial glioma in mice, and can be normalized with immunotherapy. We note that ablation of CCR6 remarkably improves response of glioma-bearing mice to anti-PD-1 therapy. Mechanistically, we observed a reduction in regulatory T cell immunosuppressive phenotype with CCR6 ablation, which improves CD8 T cell effector function against tumor cells. Specifically, we found that CCR6 expression marks highly glycolytic Tregs, which is a known mechanism of immunosuppression of CD8 T cells, and that ablation of CCR6 from Tregs reduces their glycolytic capacity and immunosuppressivity. Targeting the CCR6:MIP-3α axis can therefore be a promising approach to alleviate CD8 T cell immunosuppression in GBM and to improve anti-tumor response.