Immune Heterogeneity of IDH Glioma Subtypes

Abstract

The metabolic gene isocitrate dehydrogenase 1 (IDH) gene is commonly mutated in WHO grade II and III gliomas and in a minority of WHO grade IV glioblastoma (GBM). Since the recent update to the World Health Organization Classification of Tumors of the Central Nervous System, IDH mutational status is recognized as the first and most important distinction when stratifying glial tumors. It is well established that IDH mutant (IDH-mut) and IDH wild-type (IDH-wt) gliomas have distinct tumor behavior driven by different oncogenic signals and respond differently to current treatment paradigms. Less understood is the interplay between the IDH mutation with anti-tumor immunity, immunosuppression, glioma specific antigens and therapeutic biomarkers. With regard to cancer immunotherapy, relatively little attention has been paid to WHO grade II/III gliomas. By comparing the immune responses in IDH-mut and IDH-wt using The Cancer Genome Atlas (TCGA) WHO grade II and III glioma dataset, we identified a marked reduction in expression of immune related genes in IDH-mut gliomas. Furthermore, we validated our TCGA data by demonstrating fewer tumor infiltrating lymphocytes (TILs) across both effector and suppressive T cell subsets in IDH mutant gliomas, supporting the notion that IDH-mut tumors are less immunogenic. Our data indicates that the differentially expressed immune related genes in the IDH-mut subtype may confound therapeutic responses. A greater understanding of how the IDH mutation regulates host immunity may reveal new targets for a majority of WHO grade II and III gliomas.