TLR2 Promotes Glioma Immune Evasion by Downregulating MHC Class II Molecules in Microglia

Abstract Gliomas, the most common primary neoplasms in the brain, are notorious for their ability to evade the immune response. Despite microglial infiltration in gliomas, expression of MHC class II molecules in those microglia is compromised. Here, we report that Toll-like receptor 2 (TLR2) activation downregulated expression of MHC class II molecules in microglia in an orthotopic murine glioma model. TLR2-induced microglial impairment hindered the proliferation and activation of CD4+ T cells, which facilitated glioma immune evasion. TLR2-induced downregulation of MHC class II molecules was caused by suppression of the master regulator of MHC class II molecule transcription, Ciita. TLR2 activation triggered downstream MAPK/ERK1/2 signaling and loss of histone H3 acetylation at Ciita promoters, which in turn inhibited Ciita expression. In glioblastoma tissues, various endogenous TLR2 ligands, including the heat shock proteins that are endogenous TLR2 ligands, were upregulated, a response that correlated with CIITA inhibition. Thus, TLR2 promotes glioma immune-system evasion. These results advance our understanding of microglia as antigen-presenting cells in the context of glioma. In the glioma tumor microenvironment, TLR2 activation of microglia induces downregulation of microglial MHC class II expression. Impaired MHC class II expression limits T-cell–dependent antitumor immunity. Cancer Immunol Res; 6(10); 1220–33. ©2018 AACR.