Abstract
Background: Tumor microenvironment, especially infiltrating immune cell, is crucial for solid tumors including glioma. However, the hub genes as well as their effects on patient prognosis and immunotherapy efficacy remain obscure.Methods: We employed a total of 952 lower grade glioma (LGG) patients from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases, and 24 samples in our hospital for subsequent analyses. Abundances of immune infiltrates were evaluated using CIBERSORT and ImmuCellAI. Their correlations with prognosis were assessed by log-rank test. Immune infiltration-related hub genes were obtained from overlapped differential expressed genes (DEGs) in various subsets of survival-related immune cell types. The risk signature was constructed by Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis. The functional analyses were estimated by GVSA and Gene Set Enrichment Analysis (GSEA) algorithms. And protein–protein interaction enrichment analysis was carried out with the Metascape database integrating STRING, BioGrid, OmniPath, and InWeb_IM.Results: Among the 21 infiltrates, the abundances of five immune infiltrates were correlated with overall survival (OS) in LGG patients. Higher abundances of naïve CD4+ T cells (p = 0.002), activated mast cells (p = 0.015), and monocytes (p = 0.014) were correlated with better prognosis, while higher abundances of resting memory CD4+ T cells (p = 0.015) and M1 macrophages (p = 0.020) correlated with poorer OS. We finally obtained 44 hub genes and constructed an immune infiltration-related signature (IIRS). The IIRS correlates with clinicopathological characteristics and exhibited potential power in predicting the immunotherapy efficacy. The IRRS correlates with cancer related pathways, especially “epithelial-mesenchymal transition (EMT),” and cytotoxic T lymphocytes.Conclusion: Our study constructed and validated a novel signature for risk stratification and prediction of immunotherapy response in grade II and III gliomas, which was closely associated with glioma immune microenvironment and could serve as a promising prognostic biomarker for glioma patients.
Highlights
MATERIALS AND METHODSGliomas are the most common primary tumors of the central nervous system that arise from the intrinsic constituent cells of the brain (Sanai et al, 2005)
Predictive biomarkers recognized and used in clinics mainly included isocitrate dehydrogenase (IDH) mutation, the discovery of which constituted a key breakthrough in the understanding of WHO grade II/III gliomas (Yan et al, 2009)
Novel pathogenesis-based treatments targeting oncogenic signaling pathways such as BRAF mutation (Robinson et al, 2014), epidermal growth factor receptor (EGFR) amplification (Phillips et al, 2016), and fibroblast growth factor receptor (FGFR)-TACC fusion demonstrate a potential for lower grade gliomas (LGG) elimination (Stefano et al, 2015)
Summary
Gliomas are the most common primary tumors of the central nervous system that arise from the intrinsic constituent cells of the brain (Sanai et al, 2005). They have historically been classified on the basis of their microscopic and immunohistochemical resemblance and have been graded according to histological features indicative of biological aggressiveness. Genome-wide molecular-profiling studies have revealed comprehensive genomic landscapes for major types of gliomas (Suzuki et al, 2015). These developments have identified novel biomarkers for improved tumor classification and promising therapeutic targets. The hub genes as well as their effects on patient prognosis and immunotherapy efficacy remain obscure
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