Impact of redox-related genes on tumor microenvironment immune characteristics and prognosis of high-grade gliomas

Yunbo Yuan; Mingrong Zuo; Shuxin Zhang; Siliang Chen; Wentao Feng; Zhihao Wang; Mina Chen; Yanhui Liu

doi:10.3389/fncel.2023.1155982

Impact of redox-related genes on tumor microenvironment immune characteristics and prognosis of high-grade gliomas

Front Cell Neurosci. 2023 May 12:17:1155982. doi: 10.3389/fncel.2023.1155982. eCollection 2023.

Authors

Yunbo Yuan^#¹, Mingrong Zuo^#¹, Shuxin Zhang¹, Siliang Chen¹, Wentao Feng¹, Zhihao Wang¹, Mina Chen², Yanhui Liu¹

Affiliations

¹ Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China.
² Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

^# Contributed equally.

Abstract

Introduction: High-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).

Methods: To 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).

Results: Seventy-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.

Conclusion: Briefly, 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.

Keywords: glioma; immune; microenvironment; prognosis; redox.

Grants and funding

This study was supported by the Clinical Research Innovation Project, West China Hospital, Sichuan University (19HXCX009 to YL), Post-Doctor Research Project, West China Hospital, Sichuan University (2020HXBH159 to MZ), Sichuan Provincial Foundation of Science and Technology (2023NSFSC1867 to SZ), and the Science and Technology Project, Technology Innovation Research and Development Project, Chengdu (2022-YF05-01456-SN to MC).