Abstract 5704: IDH2 mutation reduce radiotherapy induced immune response in glioblastoma by affecting micronucleus formation

Abstract

Abstract DNA methylation is the most abundant epigenetic modification, it plays a critical role in tissue homeostasis, genomic stability, and mitotic fidelity. Isocitrate dehydrogenase genes (IDH1/2) are non-redundantly mutated in several types of cancers including Glioblastoma (GBM), and their mutation induces a DNA hypermethylation phenotype. Radiotherapy (RT), either alone or in combination with other treatments, forms a primary intervention for GBM but the full scope of how IDH1/2 mutations influence this response are not known. In this work, we demonstrate that IDH2 mutation reduces the formation of post-RT micronuclei (MN), small DNA bodies in the cytoplasm distinct from the primary nucleus. Previously, MN has been found to recruit the pattern recognition receptor cGAS to activate an interferon-mediated signalling cascade via STING. We demonstrate that hypermethylation induced by IDH2 mutation does not impact cGAS localization to MN but instead reduces the overall burden of MN which correlates with decreased cGAS-STING mediated transcriptional activation. Mechanistically, IDH2 mutation drives centromeric hypermethylation which stabilizes kinetochore assembly and the fidelity of mitotic chromosome segregation post radiation. We also demonstrate that a reduction of MN formation in IDH2 mutant tumors reduces synergy between RT and immune checkpoint blockade in murine glioma models. Together our data suggest that metabolic alterations in cancers directly influence mitotic fidelity and response to RT with important implications for combination treatments that capitalize on synergy with the innate cellular signalling toward the adaptive immune system. Citation Format: Sara Mahmoud Elkashef, Shirony Nicholson, Shane Harding. IDH2 mutation reduce radiotherapy induced immune response in glioblastoma by affecting micronucleus formation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5704.