Yuan Yunbo, Zuo Mingrong, Zhang Shuxin, Chen Siliang, Feng Wentao, Wang Zhihao, Chen Mina, Liu Yanhui
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China.
Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Front Cell Neurosci. 2023 May 12;17:1155982. doi: 10.3389/fncel.2023.1155982. eCollection 2023.
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).
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).
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. 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.
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.
高级别胶质瘤（HGG）是一组脑胶质瘤，其特征为对比增强、肿瘤异质性高以及临床预后差。氧化还原（redox）平衡紊乱常与肿瘤细胞及其微环境（TME）的发展相关。
为研究氧化还原平衡对HGG及其微环境的影响，我们从TCGA和CGGA数据库以及我们自己的队列中收集了HGG患者的mRNA测序和临床数据。氧化还原相关基因（ROG）被定义为MSigDB通路中带有关键词“redox”且在HGG与正常脑样本之间差异表达的基因。采用无监督聚类分析来发现ROG表达簇。还运用了过度表达分析（ORA）、基因集富集分析（GSEA）和基因集变异分析（GSVA）来了解HGG簇之间差异表达基因的生物学意义。使用CIBERSORTx和ESTIMATE来描绘肿瘤的免疫TME景观，并用TIDE来评估对免疫检查点抑制剂的潜在反应。采用最小绝对收缩和选择算子（LASSO）Cox回归构建HGG-ROG表达风险特征（GRORS）。
共发现75个ROG，利用ROG的表达谱进行一致性聚类将异柠檬酸脱氢酶突变型（IDHmut）和异柠檬酸脱氢酶野生型（IDHwt）HGG均分为具有不同预后的亚簇。功能富集分析表明，IDHmut HGG中氧化还原亚簇之间的侵袭性差异与细胞周期调控通路显著相关，而IDHwt HGG氧化还原亚簇显示出不同程度激活的免疫相关通路。对TME中免疫景观的TME分析表明，IDHmut和IDHwt HGG中侵袭性更强的氧化还原亚簇可能含有更丰富多样的肿瘤浸润免疫细胞组成，表达更高水平的免疫检查点，并且更有可能对免疫检查点阻断产生反应。接下来，我们建立了GRORS，在预测验证数据集中HGG患者1 - 3年生存率时，其曲线下面积（AUC）分别为0.787、0.884和0.917，并且结合GRORS和其他预后信息的列线图的一致性指数（C指数）达到0.835。
简而言之，我们的结果表明ROG的表达模式与HGG的预后以及TME免疫特征密切相关，并且可能作为其对免疫治疗反应的潜在指标。
