OncoImmunology (Jan 2021)
Reprogramming the immunosuppressive microenvironment of IDH1 wild-type glioblastoma by blocking Wnt signaling between microglia and cancer cells
Abstract
The vast majority (>90%) of glioblastoma (GBM) patients belong to the isocitrate dehydrogenase 1 wild type (IDH1WT) group which exhibits a poor prognosis with a median survival of less than 15 months. This study demonstrated numerous immunosuppressive genes as well as β-catenin gene, pivotal for Wnt/β-catenin signaling, were upregulated in 206 IDH1WT glioma patients using the Chinese Glioma Genome Atlas (CGGA) database. The increase in microglia with an immunosuppressive phenotype and the overexpression of β-catenin protein were further verified in IDH1WT GBM patients and IDH1WT GL261 glioma allografts. Subsequently, we found that IDH1WT GL261 cell-derived conditioned medium activated Wnt/β-catenin signaling in primary microglia and triggered their transition to an immunosuppressive phenotype. Blocking Wnt/β-catenin signaling not only attenuated microglial polarization to the immunosuppressive subtype but also reactivated immune responses in IDH1WT GBM allografts by simultaneously enhancing cytotoxic CD8+ T cell infiltration and downregulating regulatory T cells. Positron emission tomography imaging demonstrated enhanced proinflammatory activities in IDH1WT 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 IDH1WT 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 IDH1WT glioma cells and immunosuppressive microglia is important in maintaining the immunosuppressive glioma microenvironment. Blocking Wnt/β-catenin signaling is a promising complement for IDH1WT GBM treatment by improving the hostile immunosuppressive microenvironment.
Keywords
