Abstract
BackgroundGlioma is the most common malignant brain tumor in adults, with its tumor-promoting immune microenvironment always being intricate to handle with. Amounts of evidence has accumulated to suggest that alternative splicing (AS) is related to tumor immune microenvironment. However, comprehensive analysis of immune-related AS events and their clinical significance are still lacking in glioma.MethodsAS events and transcriptome data of 653 glioma patients were downloaded online. ssGSEA was performed on transcriptome data of 653 patients to divided them into low, medium and high immune cell infiltration groups. Immune-related AS events were filtrated based on this grouping. Then lasso Cox regression analysis and multivariate Cox regression analysis were done to achieve an immune-related AS events prognostic signature for glioma. Kaplan-Meier analysis, ROC analyses, univariate Cox regression and multivariate Cox regression were performed to reveal the independent prognostic role of this signature. Meanwhile, a nomogram was constructed to achieved better prognostic value for glioma patients. Besides, functional enrichment analyses and correlation analyses with immune cells infiltration were used to validated the immune-related characteristic of this signature.Results36 immune-related AS events were achieved based on the grouping mentioned above. A nine-immune-related alternative splicing event signature was built for glioma patients. This signature showed an independent prognostic value and a nomogram containing gender, age, Karnofsky performance score, grade, IDH status, MGMT promoter status and risk score derived from the signature was constructed with a higher predictive ability for overall survival. Association with the infiltration of immune cell subtypes was validated and functional enrichment analysis found that the signature was mainly enriched in immune-related and pro-tumor functions.ConclusionOur research presented all immune-related AS events in glioma, identified an immune-related prognostic AS events risk model and a nomogram was constructed to predict the prognosis individually and more precisely. Tight connection was verified between this signature and clinical characteristics. Also, immune cells infiltration and immune checkpoints expression level were proved to link to risk scores, which enhanced the understanding of relationship between AS events and glioma immune microenvironment, firstly revealing the potential role of AS in immunotherapy of glioma.
Highlights
Glioma is the most common primary brain tumor which accounts for 50% to 60% in the central nervous system [1]
653 diffuse glioma samples were obtained from the the Cancer Genome Atlas (TCGA) database
Stromal score, ESTIMATE score, and tumor purity of the three subtypes, we found that there was a significantly positive correlation between immune cell infiltration groups and ESTIMATE score, and the same was true of immune score and stromal score (p
Summary
Glioma is the most common primary brain tumor which accounts for 50% to 60% in the central nervous system [1]. Immune suppressive microenvironment, a complex system consisting of tumor cells and non-tumor immune cells, was proved as a key factor for tumor development [4]. Genome-wide studies showed that 90% to 95% of human genes undergo some level of alternative splicing, and almost one-third of them were proved to generate multiple protein isoforms [8, 9]. The importance of AS on tumor immunity is gradually being widely supported and increasing analysis of AS events have demonstrated the independent oncogenic effects that could be relevant to the suppressive immune microenvironment in cancers [12,13,14]. Glioma is the most common malignant brain tumor in adults, with its tumorpromoting immune microenvironment always being intricate to handle with. Comprehensive analysis of immune-related AS events and their clinical significance are still lacking in glioma
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