Abstract
Diffuse glioma is one of the most prevalent malignancies of the brain, with high heterogeneity of tumor-infiltrating immune cells. However, immune-associated subtypes of diffuse glioma have not been determined, nor has the effect of different immune-associated subtypes on disease prognosis and immune infiltration of diffuse glioma patients. We retrieved the expression profiles of immune-related genes from The Cancer Genome Atlas (TCGA) (n = 672) and GSE16011 (n = 268) cohorts and used them to identify subtypes of diffuse glioma via Consensus Cluster Plus analysis. We used the limma, clusterProfiler, ESTIMATE, and survival packages of R for differential analysis, functional enrichment, immune and stromal score evaluation respectively in three subtypes, and performed log-rank tests in immune subtypes of diffuse glioma. The immune-associated features of diffuse glioma in the two cohorts were characterized via bioinformatic analyses of the mRNA expression data of immune-related genes. Three subtypes (C1–3) of diffuse glioma were identified from TCGA data, and were verified using the GSE16011 cohort. We then evaluated their immune characteristics and clinical features. Our mRNA profiling analyses indicated that the different subtypes of diffuse glioma presented differential expression profile of specific genes and signal pathways in the TCGA cohort. Patients with subtype C1, who were mostly diagnosed with grade IV glioma, had poorer outcomes than patients with subtype C2 or C3. Subtype C1 was characterized by a higher degree of immune cell infiltration as estimated by GSVA, and more frequent wildtype IDH1. By contrast, subtype C3 included more grade II and IDH1-mutated glioma, and was associated with more infiltration of CD4+T cells. Most subtype C2 had the features between subtypes C1 and C3. Meanwhile, immune checkpoints and their ligand molecules, including PD1/(PD-L1/PDL2), CTLA4/(CD80/CD86), and B7H3/TLT2, were significantly upregulated in subtype C1 and downregulated in subtype C3. In addition, patients with subtype C1 exhibited more frequent gene mutations. Univariate and multivariate Cox regression analyses revealed that diffuse glioma subtype was an effective, independent, and better prognostic factor. Therefore, we established a novel immune-related classification of diffuse glioma, which provides potential immunotherapy targets for diffuse glioma.
Highlights
Diffuse glioma is by far the most prevalent type of primary central nervous system (CNS) malignant tumor, which accounts for >60% of all primary brain tumors [1]
Overall, based on the gene expression profiles, we identified three immune subtypes that were associated with clinical outcomes
We investigated the correlation of the diffuse glioma subtypes with macrophage subtypes in The Cancer Genome Atlas (TCGA) cohort using the CIBERSORT algorithm from the Tumor IMmune Estimation Resource (TIMER) online database
Summary
Diffuse glioma is by far the most prevalent type of primary central nervous system (CNS) malignant tumor, which accounts for >60% of all primary brain tumors [1]. The 2016 World Health Organization (WHO) Classification of CNS tumors categorizes diffuse gliomas into WHO grades II, III, and IV glioma, including oligodendrogliomas, astrocytomas, oligoastrocytomas, and glioblastomas multiforme (GBMs). The prognosis of patients with diffuse glioma varies significantly depending on the tumor grade, with median survival ranging from 1 to 15 years [4]. Patients with grade II or III glioma have a relatively better prognosis, with a median survival of >7 years [6]; with frequent disease progression, grade II–III gliomas recur as tumors with higher grades and become resistant to therapy [7]. Traditional treatments alone have not improved patient prognosis, and novel treatment strategies for patients with diffuse glioma are warranted
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