Impact of redox-related genes on tumor microenvironment immune characteristics and prognosis of high-grade gliomas
IntroductionHigh-grade glioma (HGG) defines a group of brain gliomas characterized by contrast enhancement, high tumor heterogeneity, and poor clinical outcome. Disturbed reduction–oxidation (redox) balance has been frequently associated with the development of tumor cells and their microenvironment...
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2023.1155982/full |
| _version_ | 1797828916391444480 |
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| author | Yunbo Yuan Mingrong Zuo Shuxin Zhang Siliang Chen Wentao Feng Zhihao Wang Mina Chen Yanhui Liu |
| author_facet | Yunbo Yuan Mingrong Zuo Shuxin Zhang Siliang Chen Wentao Feng Zhihao Wang Mina Chen Yanhui Liu |
| author_sort | Yunbo Yuan |
| collection | DOAJ |
| description | IntroductionHigh-grade glioma (HGG) defines a group of brain gliomas characterized by contrast enhancement, high tumor heterogeneity, and poor clinical outcome. Disturbed reduction–oxidation (redox) balance has been frequently associated with the development of tumor cells and their microenvironment (TME).MethodsTo study the influence of redox balance on HGGs and their microenvironment, we collected mRNA-sequencing and clinical data of HGG patients from TCGA and CGGA databases and our own cohort. Redox-related genes (ROGs) were defined as genes in the MSigDB pathways with keyword “redox” that were differentially expressed between HGGs and normal brain samples. Unsupervised clustering analysis was used to discover ROG expression clusters. Over-representation analysis (ORA), gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were also employed to understand the biological implication of differentially expressed genes between HGG clusters. CIBERSORTx and ESTIMATE were used to profile the immune TME landscapes of tumors, and TIDE was used to evaluated the potential response to immune checkpoint inhibitors. Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression was used to construct HGG-ROG expression risk signature (GRORS).ResultsSeventy-five ROGs were found and consensus clustering using the expression profile of ROGs divided the both IDH-mutant (IDHmut) and IDH-wildtype (IDHwt) HGGs into subclusters with different prognosis. Functional enrichment analysis revealed that the differential aggressiveness between redox subclusters in IDHmut HGGs were significantly associated with cell cycle regulation pathways, while IDHwt HGG redox subclusters showed differentially activated immune-related pathways. In silico TME analysis on immune landscapes in the TME showed that the more aggressive redox subclusters in both IDHmut and IDHwt HGGs may harbor a more diverse composition of tumor-infiltrating immune cells, expressed a higher level of immune checkpoints and were more likely to respond to immune checkpoint blockade. Next, we established a GRORS which showed AUCs of 0.787, 0.884, and 0.917 in predicting 1–3-year survival of HGG patients in the held-out validation datasets, and the C-index of a nomogram combining the GRORS and other prognostic information reached 0.835.ConclusionBriefly, our results suggest that the expression pattern of ROGs was closely associated with the prognosis as well as the TME immune profile of HGGs, and may serve as a potential indicator for their response to immunotherapies. |
| first_indexed | 2024-04-09T13:13:10Z |
| format | Article |
| id | doaj.art-26c57bda94d949fcaf6924a5c53c27ef |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-04-09T13:13:10Z |
| publishDate | 2023-05-01 |
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| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-26c57bda94d949fcaf6924a5c53c27ef2023-05-12T06:03:34ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022023-05-011710.3389/fncel.2023.11559821155982Impact of redox-related genes on tumor microenvironment immune characteristics and prognosis of high-grade gliomasYunbo Yuan0Mingrong Zuo1Shuxin Zhang2Siliang Chen3Wentao Feng4Zhihao Wang5Mina Chen6Yanhui Liu7Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Neurosurgery, West China Hospital, Sichuan University, Chengdu, ChinaIntroductionHigh-grade glioma (HGG) defines a group of brain gliomas characterized by contrast enhancement, high tumor heterogeneity, and poor clinical outcome. Disturbed reduction–oxidation (redox) balance has been frequently associated with the development of tumor cells and their microenvironment (TME).MethodsTo study the influence of redox balance on HGGs and their microenvironment, we collected mRNA-sequencing and clinical data of HGG patients from TCGA and CGGA databases and our own cohort. Redox-related genes (ROGs) were defined as genes in the MSigDB pathways with keyword “redox” that were differentially expressed between HGGs and normal brain samples. Unsupervised clustering analysis was used to discover ROG expression clusters. Over-representation analysis (ORA), gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were also employed to understand the biological implication of differentially expressed genes between HGG clusters. CIBERSORTx and ESTIMATE were used to profile the immune TME landscapes of tumors, and TIDE was used to evaluated the potential response to immune checkpoint inhibitors. Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression was used to construct HGG-ROG expression risk signature (GRORS).ResultsSeventy-five ROGs were found and consensus clustering using the expression profile of ROGs divided the both IDH-mutant (IDHmut) and IDH-wildtype (IDHwt) HGGs into subclusters with different prognosis. Functional enrichment analysis revealed that the differential aggressiveness between redox subclusters in IDHmut HGGs were significantly associated with cell cycle regulation pathways, while IDHwt HGG redox subclusters showed differentially activated immune-related pathways. In silico TME analysis on immune landscapes in the TME showed that the more aggressive redox subclusters in both IDHmut and IDHwt HGGs may harbor a more diverse composition of tumor-infiltrating immune cells, expressed a higher level of immune checkpoints and were more likely to respond to immune checkpoint blockade. Next, we established a GRORS which showed AUCs of 0.787, 0.884, and 0.917 in predicting 1–3-year survival of HGG patients in the held-out validation datasets, and the C-index of a nomogram combining the GRORS and other prognostic information reached 0.835.ConclusionBriefly, our results suggest that the expression pattern of ROGs was closely associated with the prognosis as well as the TME immune profile of HGGs, and may serve as a potential indicator for their response to immunotherapies.https://www.frontiersin.org/articles/10.3389/fncel.2023.1155982/fullgliomaimmuneprognosisredoxmicroenvironment |
| spellingShingle | Yunbo Yuan Mingrong Zuo Shuxin Zhang Siliang Chen Wentao Feng Zhihao Wang Mina Chen Yanhui Liu Impact of redox-related genes on tumor microenvironment immune characteristics and prognosis of high-grade gliomas Frontiers in Cellular Neuroscience glioma immune prognosis redox microenvironment |
| title | Impact of redox-related genes on tumor microenvironment immune characteristics and prognosis of high-grade gliomas |
| title_full | Impact of redox-related genes on tumor microenvironment immune characteristics and prognosis of high-grade gliomas |
| title_fullStr | Impact of redox-related genes on tumor microenvironment immune characteristics and prognosis of high-grade gliomas |
| title_full_unstemmed | Impact of redox-related genes on tumor microenvironment immune characteristics and prognosis of high-grade gliomas |
| title_short | Impact of redox-related genes on tumor microenvironment immune characteristics and prognosis of high-grade gliomas |
| title_sort | impact of redox related genes on tumor microenvironment immune characteristics and prognosis of high grade gliomas |
| topic | glioma immune prognosis redox microenvironment |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2023.1155982/full |
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