IDH1 mutation impairs antiviral response and potentiates oncolytic virotherapy in glioma

IDH1 mutations frequently occur early in human glioma. While IDH1 mutation has been shown to promote gliomagenesis via DNA and histone methylation, little is known regarding its regulation in antiviral immunity. Here, we discover that IDH1 mutation inhibits virus-induced interferon (IFN) antiviral responses in glioma cells. Mechanistically, D2HG produced by mutant IDH1 enhances the binding of DNMT1 to IRF3/7 promoters such that IRF3/7 are downregulated, leading to impaired type I IFN response in glioma cells, which enhances the susceptibility of gliomas to viral infection. Furthermore, we identify DNMT1 as a potential biomarker predicting which IDH1mut gliomas are most likely to respond to oncolytic virus. Finally, both D2HG and ectopic mutant IDH1 can potentiate the replication and oncolytic efficacy of VSV Delta 51 in female mouse models. These findings reveal a pivotal role for IDH1 mutation in regulating antiviral response and demonstrate that IDH1 mutation confers sensitivity to oncolytic virotherapy. The role of human glioma IDH1 mutations in regulation of antiviral response is unclear. Here, the authors show that D2HG produced by mutant IDH1 inhibits IFN antiviral responses in glioma cells, which confers sensitivity to oncolytic virotherapy.

Automated summary

IDH1 mutation inhibits antiviral interferon responses in glioma cells and confers sensitivity to oncolytic virotherapy.