Reprogramming the immunosuppressive microenvironment of IDH1 wild-type glioblastoma by blocking Wnt signaling between microglia and cancer cells

The vast majority (>90%) of glioblastoma (GBM) patients belong to the isocitrate dehydrogenase 1 wild type (IDH1(WT)) group which exhibits a poor prognosis with a median survival of less than 15 months. This study demonstrated numerous immunosuppressive genes as well as beta-catenin gene, pivotal for Wnt/beta-catenin signaling, were upregulated in 206 IDH1(WT) glioma patients using the Chinese Glioma Genome Atlas (CGGA) database. The increase in microglia with an immunosuppressive phenotype and the overexpression of beta-catenin protein were further verified in IDH1(WT) GBM patients and IDH1(WT) GL261 glioma allografts. Subsequently, we found that IDH1(WT) GL261 cell-derived conditioned medium activated Wnt/beta-catenin signaling in primary microglia and triggered their transition to an immunosuppressive phenotype. Blocking Wnt/beta-catenin signaling not only attenuated microglial polarization to the immunosuppressive subtype but also reactivated immune responses in IDH1(WT) GBM allografts by simultaneously enhancing cytotoxic CD8(+) T cell infiltration and downregulating regulatory T cells. Positron emission tomography imaging demonstrated enhanced proinflammatory activities in IDH1(WT) GBM allografts after the blockade of Wnt signaling. Finally, gavage administration of a Wnt signaling inhibitor significantly restrained tumor proliferation and improved the survival of model mice bearing IDH1(WT) GBM allografts. Depletion of CD8(+) T cells remarkably abrogated the therapeutic efficacy induced by the Wnt signaling inhibitor. Overall, the present work indicates that the crosstalk between IDH1(WT) glioma cells and immunosuppressive microglia is important in maintaining the immunosuppressive glioma microenvironment. Blocking Wnt/beta-catenin signaling is a promising complement for IDH1(WT) GBM treatment by improving the hostile immunosuppressive microenvironment.