Abstract
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are common in gliomas. 50-80% of WHO II/III gliomas possess IDH1/IDH2 mutation. Methylation-related transcriptional repression is a feature of IDH mutant (IDHmut) tumors. Epigenetic repression of natural killer (NK) cell ligands is a common occurrence in cancer, but it is unknown if this occurs in primary brain tumors. Here, we demonstrate transcriptional repression of NKG2D activating ligands (NKG2DLs) in IDHmut gliomas, and correlate this with decreased susceptibility of IDHmut cells to natural killer (NK) cell-mediated cytolysis in vitro. Our data suggest that NK cell-astrocyte contact is required for production of Th1 cytokines IFN-γ and TNF-α, and that production of these cytokines is limited in IDHmut astrocytes. We also show that NKG2DL-specific antibody blockade can result in significant reduction in NK-cell mediated cytolysis in vitro. Furthermore, we infect IDHmut cells with JDNI7 virus containing ULBP3 plasmid DNA to induce overexpression of this ligand. Upon ULBP3 overexpression, these cells are significantly more sensitive to NK-cell mediated lysis. Taken together, our data suggest a potential immune surveillance role for the NKG2DL, ULBP3, during IDHmut gliomagenesis.