ISG20 promotes local tumor immunity and contributes to poor survival in human glioma

Gao, Mengqi; Lin, Yi; Liu, Xing; Li, Yiming; Zhang, Chuanbao; Wang, Zheng; Wang, Zhiliang; Wang, Yulin; Guo, Zongze

Glioma is the most common and lethal type of malignancy in the primary central nervous system (CNS). 1 Although patients with low-grade gliomas (LGGs) have a more favorable prognosis than those with glioblastomas (GBMs), many tend to progress to a higher grade, leading to poor survival. 2 Nevertheless, the outcome of glioma patients is highly variable, even among those with the same tumor grade. 3 Recent analyses demonstrated that an IDH1/2 mutation, encoding isocitrate dehydrogenase (IDH) gene, occurs early in gliomagenesis, affecting a common glial precursor cell population. 4 Patients with tumors harboring an IDH1/2 mutation (IDHmut) show significantly longer survival than those expressing wild-type IDH1/2 (IDHwt). [5] [6] [7] IDH mutation leads to a CpG island methylator phenotype (CIMP) by modulating the methylation patterns on a genome-wide scale, changing transcriptional programs and altering the differentiation state. 8 CIMP is associated with microsatellite instability and longer survival in several cancers. 6, 7, [9] [10] [11] [12] [13] IDHmut and IDHwt tumors differ with regards to various biological processes, including immune cell infiltration. [14] [15] [16] [17] Human IDH1-mutant gliomas have less infiltrating immune cells than IDH1-wild type gliomas, with global depletion of immune infiltrates, including microglia, macrophages, dendritic cells, B cells, and T cells. Accordingly, early IDHmut glioma progenitor cells have suppressed immunity compared with IDHwt cells, 4, 15, 18 which may be responsible for their improved clinical outcomes. 15 Moreover, IDHmut tumors have reduced expression of cytotoxic T lymphocyte-associated genes and interferon (IFN)-γ-inducible chemokines, as well as suppressed accumulation of T cells in the tumor compared with IDHwt tumors. 16 IDHwt gliomas are also characterized by more prominent regulatory T cell infiltration and higher programmed death-ligand 1 (PD-L1) expression levels than IDHmut cases. 17 Although IDH status clearly appears to affect the immune state and progression of glioma, the underlying mechanisms remain unclear. To elucidate these mechanisms and identify the candidate prognostic and/or therapeutic markers, we investigated the differential expression of immune-related genes and their role in glioma progression. In particular, we collected clinical and transcriptome (RNA-seq) data from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases, including 932 glioma samples. We then determined the differentially expressed immune-related genes according to IDH mutation status, analyzed separately for LGG and GBM cases, and performed pathway enrichment analysis for functional annotation.