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Immune-related genes with APA in microenvironment indicate risk stratification and clinical prognosis in grade II/III gliomas.

ABSTRACT: Tumor microenvironment and alternative polyadenylation (APA) have drawn more attention in cancer research. However, their roles in grade II and III gliomas, termed as lower-grade glioma (LGG) in this study, remain to be fully elucidated. Here, we conducted this study and found that stromal and immune scores were elevated in higher grade and isocitrate dehydrogenase (IDH) wild-type glioma. Besides, higher stromal and immune scores indicated a poor prognosis in patients with LGG. APA events in immune-related genes were associated with overall survival, RNA expression, IDH mutation, and disease-free survival. Patients in the high-risk group had poor prognoses, and the risk score could be used to predict the survival rate. The risk score was positively correlated with the expression of immune checkpoints, inflammatory cytokines, and infiltrated immune cells. Moreover, risk stratification could predict the efficacy of radiotherapy and provide a reference for the treatment of grade III glioma. Our study revealed that immune-related genes with APA events in the microenvironment could predict risk stratification and clinical prognosis in patients with LGG.

SUBMITTER: Xu S

PROVIDER: S-EPMC7900014 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Immune-related genes with APA in microenvironment indicate risk stratification and clinical prognosis in grade II/III gliomas.

Xu Shengchao S Tang Lu L Dai Gan G Luo Chengke C Liu Zhixiong Z

Molecular therapy. Nucleic acids 20210204

Tumor microenvironment and alternative polyadenylation (APA) have drawn more attention in cancer research. However, their roles in grade II and III gliomas, termed as lower-grade glioma (LGG) in this study, remain to be fully elucidated. Here, we conducted this study and found that stromal and immune scores were elevated in higher grade and isocitrate dehydrogenase (IDH) wild-type glioma. Besides, higher stromal and immune scores indicated a poor prognosis in patients with LGG. APA events in imm ...[more]

PMID: 33665000

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Project description: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.

Project description:BackgroundImmunogenic cell death (ICD) is a form of cell death that elicits immune responses against the antigens found in dead or dying tumor cells. Growing evidence implies that ICD plays a significant role in triggering antitumor immunity. The prognosis for glioma remains poor despite many biomarkers being reported, and identifying ICD-related biomarkers is imminent for better-personalized management in patients with lower-grade glioma (LGG).Materials and methodsWe identified ICD-related differentially expressed genes (DEGs) by comparing gene expression profiles obtained across Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) cohorts. On the foundation of ICD-related DEGs, two ICD-related clusters were identified through consensus clustering. Then, survival analysis, functional enrichment analysis, somatic mutation analysis, and immune characteristics analysis were performed in the two ICD-related subtypes. Additionally, we developed and validated a risk assessment signature for LGG patients. Finally, we selected one gene (EIF2AK3) from the above risk model for experimental validation.Results32 ICD-related DEGs were screened, dividing the LGG samples from the TCGA database into two distinct subtypes. The ICD-high subgroup showed worse overall survival (OS), greater immune infiltration, more active immune response process, and higher expression levels of HLA genes than the ICD-low subgroup. Additionally, nine ICD-related DEGs were identified to build the prognostic signature, which was highly correlated with the tumor-immune microenvironment and could unambiguously be taken as an independent prognostic factor and further verified in an external dataset. The experimental results indicated that EIF2AK3 expression was higher in tumors than paracancerous tissues, and high-expression EIF2AK3 was enriched in WHO III and IV gliomas by qPCR and IHC, and Knockdown of EIF2AK3 suppressed cell viability and mobility in glioma cells.ConclusionWe established novel ICD-related subtypes and risk signature for LGG, which may be beneficial to improving clinical outcome prediction and guiding individualized immunotherapy.

Project description:Grade II and III gliomas are heterogeneous and aggressive diseases. More efficient prognosis models and treatment methods are needed. This study aims to construct a new risk model and propose a new strategy for grade II and III gliomas. The data were downloaded from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), gene set enrichment analysis (GSEA), and the EMTome website for analysis. The Human Cell Landscape website and the Genomics of Drug Sensitivity in Cancer website were used for single-cell analysis and drug susceptibility analysis. Gene set enrichment analysis, gene function enrichment analysis, univariate and multivariate Cox regression analyses, Pearson's correlation analysis, log-rank test, Kaplan-Meier survival analysis, and ROC analysis were performed. We constructed an immune-related prognostic model associated with the isocitrate dehydrogenase 1 (IDH1) mutation status. By analyzing the immune microenvironment of patients with different risk scores, we found that high-risk patients were more likely to have an inflammatory immune microenvironment and a higher programmed death ligand-1 (PD-L1) expression level. Epithelial-mesenchymal transition (EMT)-related gene sets were significantly enriched in the high-risk group, and the epithelial-mesenchymal transition phenotype was associated with a decrease in CD8+ T cells and an increase in M2 macrophages. Transforming growth factor-β (TGF-β) signaling was the most important signaling in inducing epithelial-mesenchymal transition, and TGFB1/TGFBR1 was correlated with an increase in CD8+ T cytopenia and M2 macrophages. Survival analysis showed that simultaneous low expression of TGFBR1 and PD-L1 had better survival results. Through single-cell analysis, we found that TGFB1 is closely related to microglia and macrophages, especially M2 macrophages. Finally, we discussed the sensitivity of TGFB1 inhibitors in gliomas using cell line susceptibility data. These results demonstrated a potential immunotherapy strategy in combination with the TGFB1/TGFBR1 inhibitor and PD-1/PD-L1 inhibitor for grade II and III gliomas.

Dataset Information

Immune-related genes with APA in microenvironment indicate risk stratification and clinical prognosis in grade II/III gliomas.

Publications

Immune-related genes with APA in microenvironment indicate risk stratification and clinical prognosis in grade II/III gliomas.

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