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Immune Infiltrating Cells-Derived Risk Signature Based on Large-scale Analysis Defines Immune Landscape and Predicts Immunotherapy Responses in Glioma Tumor Microenvironment.

ABSTRACT: The glioma tumor microenvironment (TME), composed of several noncancerous cells and biomolecules is known for its complexity of cancer-immune system interaction. Given that, novel risk signature is required for predicting glioma patient responses to immunotherapy. In this study, we systematically evaluated the TME infiltration pattern of 2877 glioma samples. TME phenotypes were determined using the Partitioning Around Medoid method. Machine learning including SVM-RFE and Principal component analysis (PCA) were used to construct a TME scoring system. A total of 857 glioma samples from four datasets were used for external validation of the TME-score. The correlation of TME phenotypes and TME-scores with diverse clinicopathologic characteristics, genomic features, and immunotherapeutic efficacy in glioma patients was determined. Immunohistochemistry staining for the M2 macrophage marker CD68 and CD163, mast cell marker CD117, neutrophil marker CD66b, and RNA sequencing of glioma samples from the XYNS cohort were performed. Two distinct TME phenotypes were identified. High TME-score correlated with a high number of immune infiltrating cells, elevated expression of immune checkpoints, increased mutation rates of oncogenes, and poor survival of glioma patients. Moreover, high TME-score exhibited remarkable association with multiple immunomodulators that could potentially mediate immune escape of cancer. Thus, the TME-score showed the potential to predict the efficacy of anti-PD-1 immunotherapy. Univariate and multivariate analyses demonstrated the TME-score to be a valuable prognostic biomarker for gliomas. Our study demonstrated that TME could potentially influence immunotherapy efficacy in melanoma patients whereas its role in immunotherapy of glioma patients remains unknown. Therefore, a better understanding of the TME landscape in gliomas would promote the development of novel immunotherapy strategies against glioma.

SUBMITTER: Zhang N

PROVIDER: S-EPMC8418124 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective: Gliomas are the most common primary tumors in the central nervous system with a bad prognosis. Pyroptosis, an inflammatory form of regulated cell death, plays a vital role in the progression and occurrence of tumors. However, the value of pyroptosis related genes (PRGs) in glioma remains poorly understood. This study aims to construct a PRGs signature risk model and explore the correlation with clinical characteristics, prognosis, tumor microenviroment (TME), and immune checkpoints. Methods: RNA sequencing profiles and the relevant clinical data were obtained from the Chinese Glioma Genome Atlas (CGGA), the Cancer Genome Atlas (TCGA), the Repository of Molecular Brain Neoplasia Data (REMBRANDT), and the Genotype-Tissue Expression Project (GTEx-Brain). Then, the differentially expressed pyroptosis related genes (PRGs) were identified, and the least absolute shrinkage and selection operator (LASSO) and mutiCox regression model was generated using the TCGA-train dataset. Then the expression of mRNA and protein levels of PRGs signature was detected through qPCR and human protein atlas (HPA). Further, the predictive ability of the PRGs-signature, prognostic analysis, and stratification analysis were utilized and validated using TCGA-test, CGGA, and REMBRANDT datasets. Subsequently, we constructed the nomogram by combining the PRGs signature and other key clinical features. Moreover, we used gene set enrichment analysis (GSEA), GO, KEGG, the tumor immune dysfunction and exclusion (TIDE) single-sample GSEA (ssGSEA), and Immunophenoscore (IPS) to determine the relationship between PRGs and TME, immune infiltration, and predict the response of immune therapy in glioma. Results: A four-gene PRGs signature (CASP4, CASP9, GSDMC, IL1A) was identified and stratified patients into low- or high-risk group. Survival analysis, ROC curves, and stratified analysis revealed worse outcomes in the high-risk group than in the low-risk group. Correlation analysis showed that the risk score was correlated with poor disease features. Furthermore, GSEA and immune infiltrating and IPS analysis showed that the PRGs signature could potentially predict the TME, immune infiltration, and immune response in glioma. Conclusion: The newly identified four-gene PRGs signature is effective in diagnosis and could robustly predict the prognosis of glioma, and its impact on the TME and immune cell infiltrations may provide further guidance for immunotherapy.

Project description:Background: Immune-checkpoint blockade (ICB) has been routinely implemented to treat head and neck squamous cell carcinoma (HNSCC) patients. However, only a few patients benefit from immune checkpoint inhibitor (ICI) therapies. Methods: In this study, we used a combined cohort (including the GSE41613, GSE65858, TCGA, and CELL cohorts) to identify hub genes significantly associated with ICB and activated CD8+ T-cell gene signatures. We performed single-sample gene set enrichment analysis (ssGSEA) to quantify the expression of hub genes; we then constructed a novel immune signature named "the IMS" that can predict immunotherapy responsiveness, prognosis, immune infiltration, and clinical characteristics. Data from the GSE102349 external cohort and the pembrolizumab cohort obtained from a clinical trial were used to validate the efficiency of the IMS. In addition, we revealed potential mechanisms of the antitumor response by analyzing the HNSCC single-cell database. Finally, we used the LASSO algorithm to build an IMS-related risk model. Results: The high IMS group was associated with significant immune activation, better prognosis, and increased immunotherapy responsiveness; thus, the IMS potentially represents a candidate biomarker for ICB. Moreover, a tumor microenvironment with a higher IMS underwent remarkable metabolic reprogramming characterized by enrichment in the glycolysis/gluconeogenesis, oxidative phosphorylation, and citrate cycle (TCA cycle) pathways. We also revealed key information on cellular crosstalk between the IMS and other immune lineages, which may mechanistically explain immune escape. In addition, we constructed and validated a risk prediction model (CD2, TBC1D10C, and CD3E) that could stratify HNSCC patients based on survival and response to ICB treatment. Conclusion: IMS is a signature closely correlated with the tumor immune microenvironment. The findings of this study contribute to the understanding of the immune landscape in HNSCC patients. IMS may aid in the clinical management of HNSCC patients through the identification of effective immunotherapies for specific patients.

Project description:BackgroundGlioma is the most common primary brain tumor in adults and accounts for more than 70% of brain malignancies. Lipids are crucial components of biological membranes and other structures in cells. Accumulating evidence has supported the role of lipid metabolism in reshaping the tumor immune microenvironment (TME). However, the relationship between the immune TME of glioma and lipid metabolism remain poorly described.Materials and methodsThe RNA-seq data and clinicopathological information of primary glioma patients were downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA). An independent RNA-seq dataset from the West China Hospital (WCH) also included in the study. Univariate Cox regression and LASSO Cox regression model was first to determine the prognostic gene signature from lipid metabolism-related genes (LMRGs). Then a risk score named LMRGs-related risk score (LRS) was established and patients were stratified into high and low risk groups according to LRS. The prognostic value of the LRS was further demonstrated by construction of a glioma risk nomogram. ESTIMATE and CIBERSORTx were used to depicted the TME immune landscape. Tumor Immune Dysfunction and Exclusion (TIDE) was utilized to predict the therapeutic response of immune checkpoint blockades (ICB) among glioma patients.ResultsA total of 144 LMRGs were differentially expressed between gliomas and brain tissue. Finally, 11 prognostic LMRGs were included in the construction of LRS. The LRS was demonstrated to be an independent prognostic predictor for glioma patients, and a nomogram consisting of the LRS, IDH mutational status, WHO grade, and radiotherapy showed a C-index of 0.852. LRS values were significantly associated with stromal score, immune score, and ESTIMATE score. CIBERSORTx indicated remarkable differences in the abundance of TME immune cells between patients with high and low LRS risk levels. Based on the results of TIDE algorithm, we speculated that the high-risk group had a greater chance of benefiting from immunotherapy.ConclusionThe risk model based upon LMRGs could effectively predict prognosis in patients with glioma. Risk score also divided glioma patients into different groups with distinct TME immune characteristics. Immunotherapy is potentially beneficial to glioma patients with certain lipid metabolism profiles.

Project description:AimsThe dysregulation of TGF-β signaling is a crucial pathophysiological process in tumorigenesis and progression. LncRNAs have diverse biological functions and are significant participants in the regulation of tumor signaling pathways. However, the clinical value of lncRNAs related to TGF-β signaling in glioma is currently unclear.MethodsData on glioma's RNA-seq transcriptome, somatic mutation, DNA methylation data, and clinicopathological information were derived from the CGGA and TCGA databases. A prognostic lncRNA signature was constructed by Cox and LASSO regression analyses. TIMER2.0 database was utilized to deduce immune infiltration characteristics. "ELMER v.2" was used to reconstruct TF-methylation-gene regulatory network. Immunotherapy and chemotherapy response predictions were implemented by the TIDE algorithm and GDSC database, respectively. In vitro and in vivo experiments were conducted to verify the results and clarify the regulatory mechanism of lncRNA.ResultsIn glioma, a TGF-β signaling-related 15-lncRNA signature was constructed, including AC010173.1, HOXA-AS2, AC074286.1, AL592424.1, DRAIC, HOXC13-AS, AC007938.1, AC010729.1, AC013472.3, AC093895.1, AC131097.4, AL606970.4, HOXC-AS1, AGAP2-AS1, and AC002456.1. This signature proved to be a reliable prognostic tool, with high risk indicating an unfavorable prognosis and being linked to malignant clinicopathological and genomic mutation traits. Risk levels were associated with different immune infiltration landscapes, where high risk was indicative of high levels of macrophage infiltration. In addition, high risk also suggested better immunotherapy and chemotherapy response. cg05987823 was an important methylation site in glioma progression, and AP-1 transcription factor family participated in the regulation of signature lncRNA expression. AGAP2-AS1 knockdown in in vitro and in vivo experiments inhibited the proliferation, migration, and invasion of glioma cells, as well as the growth of glioma, by downregulating the expression levels of NF-κB and ERK 1/2 in the TGF-β signaling pathway.ConclusionsA prognostic lncRNA signature of TGF-β signaling was established in glioma, which can be used for prognostic judgment, immune infiltration status inference, and immunotherapy response prediction. AGAP2-AS1 plays an important role in glioma progression.

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Immune Infiltrating Cells-Derived Risk Signature Based on Large-scale Analysis Defines Immune Landscape and Predicts Immunotherapy Responses in Glioma Tumor Microenvironment.

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