Costimulatory checkpoint SLAMF8 is an independent prognosis factor in glioma.
Ontology highlight
ABSTRACT: Aims
Immune checkpoint blockade has made breakthroughs in immunotherapy for glioma. However, current immunotherapy has therapeutic benefits only in a subset of patients and accompanied by immune-related side effects. SLAMF8 is a costimulatory molecule that affects the activation of macrophages in inflammation. The study of SLAMF8 may provide new information for immunological research and treatment of glioma.Methods
CGGA and TCGA cohorts of 946 patients with RNA sequencing data and full clinical information were analyzed using R language and GraphPad Prism 7.Results
SLAMF8 was overexpressed along with malignancy progression and was a biomarker of mesenchymal subtype. As an independent prognostic factor, high SLAMF8 conferred reduced overall survival and chemotherapy resistance. SLAMF8 implied lower proportion of cancer cells along with increasing enrichment of monocytic lineage, myeloid dendritic cells. Functional analysis showed higher SLAMF8 indicated activation of antigen processing and presenting and the IFN-γ/TNF/TLR-mediated signaling. Meanwhile, coexpressing with classical checkpoint SLAMF8 aggravated immunosuppression and enhanced inflammation response.Conclusion
Our study highlighted the important role of SLAMF8 in malignancy progression, shortened survival, and immune disorders. Further research on SLAMF8 in immunosuppression and inflammation response to glioma cells could aid immunotherapy for glioma.
SUBMITTER: Zou CY
PROVIDER: S-EPMC6488888 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
Publications
Costimulatory checkpoint SLAMF8 is an independent prognosis factor in glioma.
Zou Cun-Yi CY Guan Ge-Fei GF Zhu Chen C Liu Tian-Qi TQ Guo Qing Q Cheng Wen W Wu An-Hua AH
CNS neuroscience & therapeutics 20180813 3
<h4>Aims</h4>Immune checkpoint blockade has made breakthroughs in immunotherapy for glioma. However, current immunotherapy has therapeutic benefits only in a subset of patients and accompanied by immune-related side effects. SLAMF8 is a costimulatory molecule that affects the activation of macrophages in inflammation. The study of SLAMF8 may provide new information for immunological research and treatment of glioma.<h4>Methods</h4>CGGA and TCGA cohorts of 946 patients with RNA sequencing data an ...[more]
Similar Datasets
Project description:BackgroundXRCC2, a homologous recombination-related gene, has been reported to be associated with a variety of cancers. However, its role in glioma has not been reported. This study aimed to find out the role of XRCC2 in glioma and reveal in which glioma-specific biological processes is XRCC2 involved based on thousands of glioma samples, thereby, providing a new perspective in the treatment and prognostic evaluation of glioma.MethodsThe expression characteristics of XRCC2 in thousands of glioma samples from CGGA and TCGA databases were comprehensively analyzed. Wilcox or Kruskal test was used to analyze the expression pattern of XRCC2 in gliomas with different clinical and molecular features. The effect of XRCC2 on the prognosis of glioma patients was explored by Kaplan-Meier and Cox regression. Gene set enrichment analysis (GSEA) revealed the possible cellular mechanisms involved in XRCC2 in glioma. Connectivity map (CMap) was used to screen small molecule drugs targeting XRCC2 and the expression levels of XRCC2 were verified in glioma cells and tissues by RT-qPCR and immunohistochemical staining.ResultsWe found the overexpression of XRCC2 in glioma. Moreover, the overexpressed XRCC2 was associated with a variety of clinical features related to prognosis. Cox and meta-analyses showed that XRCC2 is an independent risk factor for the poor prognosis of glioma. Furthermore, the results of GSEA indicated that overexpressed XRCC2 could promote malignant progression through involved signaling pathways, such as in the cell cycle. Finally, doxazosin, quinostatin, canavanine, and chrysin were identified to exert anti-glioma effects by targeting XRCC2.ConclusionsThis study analyzed the expression pattern of XRCC2 in gliomas and its relationship with prognosis using multiple datasets. This is the first study to show that XRCC2, a novel oncogene, is significantly overexpressed in glioma and can lead to poor prognosis in glioma patients. XRCC2 could serve as a new biomarker for glioma diagnosis, treatment, and prognosis evaluation, thus bringing new insight into the management of glioma.
| S-EPMC8164800 | biostudies-literature
Project description:Recent studies have found that cytoskeleton-associated protein 2 like (CKAP2L), an important oncogene, is involved in the biological behavior of many malignant tumors, but its function in the malignant course of glioma has not been confirmed. The main purpose of this study was to clarify the relationship between prognostic clinical characteristics of glioma patients and CKAP2L expression using data collected from the GEPIA, HPA, CGGA, TCGA, and GEO databases. CKAP2L expression was significantly increased in glioma. Further, Kaplan-Meier plots revealed that increased expression of CKAP2L was associated with shorter survival time of glioma patients in datasets retrieved from multiple databases. Cox regression analysis indicated that CKAP2L can serve as an independent risk factor but also has relatively reliable diagnostic value for the prognosis of glioma patients. The results of gene set enrichment analysis suggested that CKAP2L may play a regulatory role through the cell cycle, homologous recombination, and N-glycan biosynthesis cell signaling pathways. Several drugs with potential inhibitory effects on CKAP2L were identified in the CMap database that may have therapeutic effects on glioma. Finally, knockdown of CKAP2L inhibited the proliferation and invasion of cells by reducing the expression level of cell cycle-related proteins. This is the first study to demonstrate that high CKAP2L expression leads to poor prognosis in glioma patients, providing a novel target for diagnosis and treatment of glioma.
| S-EPMC8494202 | biostudies-literature
Project description:In recent years, studies have revealed HOXA2 as a new oncogene, but its function is unknown in gliomas. We aimed to reveal the relationship between HOXA2 and glioma based on the Chinese Glioma Genome Atlas(CGGA) and the cancer genome atlas (TCGA). HOXA2 expression data and clinically relevant information of glioma patients were obtained from the CGGA and TCGA containing 1447 glioma tissues and five non-tumor brain tissues. The Wilcox or Kruskal tests were used to detect the correlation between the HOXA2 expression level and clinical data of glioma patients. the Kaplan-Meier method were used to examine the relationship between HOXA2 and overall patient survival. Gene set enrichment analysis (GSEA) was conducted to indirectly reveal the signaling pathways involved in HOXA2, and RT-PCR was used to detect HOXA2 expression in gliomas and non-tumor brain tissues. High HOXA2 expression was found to be positively correlated with clinical grade, histological type, age, and tumor recurrence, but negatively correlated with 1p19 codeletion and isocitrate dehydrogenase mutation status.RT-PCR results showed that HOXA2 expression levels were significantly higher in tumor tissues than in non-tumor brain tissues. GSEA showed that HOXA2 promoted the activation of the activation of the JAK-STAT-signaling pathway, focal adhesion, cell-adhesion-molecules-CAMS pathway, cytosolic DNA sensing pathway, and natural killer cell-mediated cytotoxicity. This study revealed for the first time that the novel oncogene,HOXA2, leads to poor prognosis in gliomas, and can be used as a biomarker for the diagnosis and treatment of gliomas.
| S-EPMC7469623 | biostudies-literature
Project description:Gamma-interferon-inducible lysosomal thiol reductase, the only known lysosomal thiol reductase, is encoded by gene IFI30 and expressed constitutively in antigen-presenting cells. Our comprehensive study on IFI30 in gliomas found its expression to be high in glioblastomas and in gliomas with a mesenchymal subtype or wild-type isocitrate dehydrogenase, all of which indicated the malignancy and poor outcomes of gliomas. Kaplan-Meier survival analysis ascertained that high IFI30 expression conferred poor outcomes. The IFI30 expression levels also showed high efficiency in predicting 1-, 3- and 5-year overall survival. Univariable and multivariable Cox regression analyses were performed to define IFI30 as an independent prognostic marker. Biological process analysis suggested that IFI30 was involved in immune responses. ESTIMATE and CIBERSORT were applied to evaluate immune cell infiltration, with results indicating that samples with higher IFI30 expression had higher infiltration of immune cells, including regulatory T cells and M0 macrophages. Correlation analysis showed that IFI30 was significantly positively correlated with immune checkpoints that suppress effective antitumour immune responses. Immunohistochemical staining was also performed to confirm the association between IFI30 expression and the immune phenotype. The suggested correlation between high IFI30 expression and an immunosuppressive phenotype contributes to our knowledge about the glioma microenvironment and might provide clues for the development of novel therapeutic targets.
| S-EPMC7686962 | biostudies-literature
Project description:Objective: The expression, prognosis, and related mechanisms of ANXA1 are investigated in glioma, with the objective to find potential therapeutic molecular targets for glioma. Methods: We analyzed the gene expression of ANXA1 using glioma-related databases, including the Chinese Glioma Genome Atlas (CGGA) database, The Cancer Genome Atlas (TCGA) database, and the Gene Expression Omnibus (GEO) database. Moreover, we collected the sample tissues and corresponding paracancerous tissues of 23 glioma patients and then conducted a Western blot experiment to verify the expression and correlate survival of ANXA1. Moreover, we generated survival ROC curves, performing univariate and multivariate Cox analyses and the construction of the nomogram. Differential expression analysis was conducted by high and low grouping based on the median of the ANXA1 gene expression values. We conducted Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Gene Set Enrichment Analysis (GSEA) to explore possible mechanisms, and gene co-expression analysis was also performed. Results: The results showed that the ANXA1 expression level was higher in gliomas than in normal tissues, and a high expression level of ANXA1 in gliomas was associated with poorer prognosis. The independent prognosis analysis showed that the ANXA1 gene was an independent prognostic factor of glioma. In the analysis of KEGG and Gene Set Enrichment Analysis (GSEA), it is shown that ANXA1 may play an important role in glioma patients by affecting extracellular matrix (ECM)-receptor interaction and the focal adhesion signal pathway. The core genes, including COL1A1, COL1A2, FN1, ITGA1, and ITGB1, were screened for gene correlation and prognosis analysis. The expression level of the five genes was verified by qPCR in glioma. We concluded that these five core genes and ANXA1 could play a synergistic role in gliomas. Conclusion: The results indicated that a high expression level of ANXA1 leads to worse prognosis and ANXA1 is an independent prognostic factor and a potentially important target for the treatment of gliomas.
| S-EPMC9193966 | biostudies-literature
Project description:Background: Extensive research showed costimulatory molecules regulate tumor progression. Nevertheless, a small amount of literature has concentrated on the potential prognostic and therapeutic effects of costimulatory molecules in patients with glioma. Methods: The data were downloaded from The Cancer Genome Atlas (TCGA) database, Chinese Glioma Genome Atlas (CGGA) database, and Gene Expression Omnibus (GEO) database for bioinformatics analysis. R software was applied for statistical analysis. Using the FigureYa and Xiantao online tools (https://www.xiantao.love/) for mapping. Results: The Least absolute shrinkage and selection operator (LASSO) and Cox regression analysis were utilized to identify the signature consisting of five costimulatory molecules. Multivariate regression analysis revealed that the prognosis of glioma could be independently predicted by the riskscore. Furthermore, we explored clinical and genomic feature differences between the two groups. The level of tumor mutational burden (TMB) was higher in the high-risk group, while more mutation of IDH1 was observed in the low-risk group. Results of Tumor Immune Dysfunction and Exclusion (TIDE) analysis showed that high-risk patients were more prone to be responded to immunotherapy. In addition, subclass mapping analysis was performed to validate our findings and the results revealed that a significantly higher percentage of immunotherapy response rate was observed in the high-risk group. Conclusion: A novel signature with a good independent predictive capacity of prognosis was successfully identified. And our findings reveal that patients with high-risk scores were more likely to be responded to immunotherapy.
| S-EPMC9682268 | biostudies-literature
Project description:Background: Analysis of the differentially expressed genes between lower grade glioma (LGG) and glioblastoma (GBM) will identify genes involved in a more aggressive phenotype of glioma. Methods: Differentially expressed genes between GBM and LGG were identified using published datasets. Kaplan-Meier estimator was used to determine the overall survival of different groups of glioma patients. The biological functions of CDHR1 in glioma were tested using CCK-8 and trans-well assays. Results: CCDC109B, CD58, CLIC1, EFEMP2, EMP3, LAMC1, LGALS1, PDLIM1 and TNFRSF1A were over-expressed, while, CDHR1 was down-regulated in GBM in The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), GSE4412 and GSE43378 datasets. Compared with normal brain tissues, CDHR1 was down-regulated in glioma tissues. And low expression of CDHR1 was an unfavorable prognostic factor in glioma. Moreover, CDHR1 was lowly expressed in mesenchymal GBM subtype and lower expression of CDHR1 was associated with the worse clinical prognosis of GBM. Furthermore, CDHR1 was down-regulated in astrocytoma LGG subtype and low expression of CDHR1 was a bad prognosis of LGG. CDHR1 expression levels were also associated with IDH mutation. IDH mutant LGG or GBM patients were with higher CDHR1 expression. High expression of CDHR1 was a favorable prognosis in IDH mutant or IDH wild type LGG patients. CHDR1 expression was associated with MGMT methylation and CDHR1 was down-regulated in chemotherapy un-responsive LGG patients. CDHR1 was an independent prognostic factor and negatively associated with EMP3 expression. Glioma patients with low CDHR1 and high EMP3 expression had worse clinical outcomes. At last, we showed that over-expression of CDHR1 could inhibit glioma cell growth and invasion. Conclusion: Low expression of CDHR1 was an independent unfavorable prognostic factor in glioma.
| S-EPMC8317511 | biostudies-literature
Project description: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.
| S-EPMC7786360 | biostudies-literature
Project description:Glioma is the most common primary brain tumor in the human brain. The present study was designed to explore the expression of PIMREG in glioma and its relevance to the clinicopathological features and prognosis of glioma patients. The correlations of PIMREG with the infiltrating levels of immune cells and its relevance to the response to immunotherapy were also investigated. PIMREG expression in glioma was analyzed based on the GEO, TCGA, and HPA databases. Kaplan-Meier survival analysis was used to examine the predictive value of PIMREG for the prognosis of patients with glioma. The correlation between the infiltrating levels of immune cells in glioma and PIMREG was analyzed using the CIBERSORT algorithm and TIMRE database. The correlation between PIMREG and immune checkpoints and its correlation with the patients' responses to immunotherapy were analyzed using R software and the GEPIA dataset. Cell experiments were conducted to verify the action of PIMREG in glioma cell migration and invasion. We found that PIMREG expression was upregulated in gliomas and positively associated with WHO grade. High PIMREG expression was correlated with poor prognosis of LGG, prognosis of all WHO grade gliomas, and prognosis of recurrent gliomas. PIMREG was related to the infiltration of several immune cell types, such as M1 and M2 macrophages, monocytes and CD8+ T cells. Moreover, PIMREG was correlated with immune checkpoints in glioma and correlated with patients' responses to immunotherapy. KEGG pathway enrichment and GO functional analysis illustrated that PIMREG was related to multiple tumor- and immune-related pathways. In conclusion, PIMREG overexpression in gliomas is associated with poor prognosis of patients with glioma and is related to immune cell infiltrates and the responses to immunotherapy.
| S-EPMC9344140 | biostudies-literature
Project description:The overall survival of patients with lower grade glioma (LGG) varies greatly, but the current histopathological classification has limitations in predicting patients' prognosis. Therefore, this study aims to find potential therapeutic target genes and establish a gene signature for predicting the prognosis of LGG. CD44 is a marker of tumor stem cells and has prognostic value in various tumors, but its role in LGG is unclear. By analyzing three glioma datasets from Gene Expression Omnibus (GEO) database, CD44 was upregulated in LGG. We screened 10 CD44-related genes via protein-protein interaction (PPI) network; function enrichment analysis demonstrated that these genes were associated with biological processes and signaling pathways of the tumor; survival analysis showed that four genes (CD44, HYAL2, SPP1, MMP2) were associated with the overall survival (OS) and disease-free survival (DFS)of LGG; a novel four-gene signature was constructed. The prediction model showed good predictive value over 2-, 5-, 8-, and 10-year survival probability in both the development and validation sets. The risk score effectively divided patients into high- and low- risk groups with a distinct outcome. Multivariate analysis confirmed that the risk score and status of IDH were independent prognostic predictors of LGG. Among three LGG subgroups based on the presence of molecular parameters, IDH-mutant gliomas have a favorable OS, especially if combined with 1p/19q codeletion, which further confirmed the distinct biological pattern between three LGG subgroups, and the gene signature is able to divide LGG patients with the same IDH status into high- and low- risk groups. The high-risk group possessed a higher expression of immune checkpoints and was related to the activation of immunosuppressive pathways. Finally, this study provided a convenient tool for predicting patient survival. In summary, the four prognostic genes may be therapeutic targets and prognostic predictors for LGG; this four-gene signature has good prognostic prediction ability and can effectively distinguish high- and low-risk patients. High-risk patients are associated with higher immune checkpoint expression and activation of the immunosuppressive pathway, providing help for screening immunotherapy-sensitive patients.
| S-EPMC7769121 | biostudies-literature