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

Oncoimmunology
Dandan FanCong Li

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 adm...Continue Reading

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CGGA
GraphPad Prism
Snapgene

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