IDH1 mutation impairs antiviral response and potentiates oncolytic virotherapy in glioma

Xueqin Chen, Jun Liu, Yuqin Li, Yuequan Zeng, Fang Wang, Zexiong Cheng, Hao Duan, Guopeng Pan, Shangqi Yang, Yuling Chen, Qing Li, Xi Shen, Ying Li, Zixi Qin, Jiahong Chen, Youwei Huang, Xiangyu Wang, Yuli Lu, Minfeng Shu, Yubo Zhang, Guocai Wang, Kai Li, Xi Lin (), Fan Xing () and Haipeng Zhang ()
Additional contact information
Xueqin Chen: Jinan University
Jun Liu: Jinan University
Yuqin Li: Jinan University
Yuequan Zeng: Jinan University
Fang Wang: Jinan University
Zexiong Cheng: Jinan University
Hao Duan: Sun Yat-sen University Cancer Center
Guopeng Pan: Jinan University
Shangqi Yang: Jinan University
Yuling Chen: Fudan University
Qing Li: Jinan University
Xi Shen: Jinan University
Ying Li: Jinan University
Zixi Qin: Jinan University
Jiahong Chen: Jinan University
Youwei Huang: Jinan University
Xiangyu Wang: Jinan University
Yuli Lu: Jinan University
Minfeng Shu: Fudan University
Yubo Zhang: Jinan University
Guocai Wang: Jinan University
Kai Li: The Sixth Affiliated Hospital of Sun Yat-sen University
Xi Lin: Jinan University
Fan Xing: Southern Medical University
Haipeng Zhang: Jinan University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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 VSVΔ51 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.

Date: 2023
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DOI: 10.1038/s41467-023-42545-3

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