Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, China.
The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
Front Immunol. 2022 Sep 30;13:869061. doi: 10.3389/fimmu.2022.869061. eCollection 2022.
Although isocitrate dehydrogenase (IDH) mutation serves as a prognostic signature for routine clinical management of glioma, nearly 90% of glioblastomas (GBM) patients have a wild-type IDH genotype (IDH) and lack reliable signatures to identify distinct entities.
To develop a robust prognostic signature for IDH GBM patients, we retrospectively analyzed 4 public datasets of 377 primary frozen tumor tissue transcriptome profiling and clinical follow-up data. Samples were divided into a training dataset (204 samples) and a validation (173 samples) dataset. A prognostic signature consisting of 21 metabolism-related gene pairs (MRGPs) was developed based on the relative ranking of single-sample gene expression levels. GSEA and immune subtype analyses were performed to reveal differences in biological processes between MRGP risk groups. The single-cell RNA-seq dataset was used to examine the expression distribution of each MRG constituting the signature in tumor tissue subsets. Finally, the association of MRGs with tumor progression was biologically validated in orthotopic GBM models.
The metabolic signature remained an independent prognostic factor (hazard ratio, 5.71 [3.542-9.218], < 0.001) for stratifying patients into high- and low-risk levels in terms of overall survival across subgroups with MGMTp methylation statuses, expression subtypes, and chemo/ratio therapies. Immune-related biological processes were significantly different between MRGP risk groups. Compared with the low-risk group, the high-risk group was significantly enriched in humoral immune responses and phagocytosis processes, and had more monocyte infiltration and less activated DC, NK, and γδ T cell infiltration. scRNA-seq dataset analysis identified that the expression levels of 5 MRGs (ABCA1, HMOX1, MTHFD2, PIM1, and PTPRE) in TAMs increased with metabolic risk. With tumor progression, the expression level of ABCA1 in TAMs was positively correlated with the population of TAMs in tumor tissue. Downregulation of ABCA1 levels can promote TAM polarization towards an inflammatory phenotype and control tumor growth.
The metabolic signature is expected to be used in the individualized management of primary IDH GBM patients.
虽然异柠檬酸脱氢酶（IDH）突变可作为胶质母细胞瘤（GBM）常规临床管理的预后标志，但近 90%的 GBM 患者存在野生型 IDH 基因型（IDH），缺乏可靠的标志物来识别不同的实体。
为了为 IDH GBM 患者开发稳健的预后标志物，我们回顾性分析了 4 个公共数据集的 377 个原发性冷冻肿瘤组织转录组分析和临床随访数据。样本分为训练数据集（204 个样本）和验证数据集（173 个样本）。基于单个样本基因表达水平的相对排序，开发了一个由 21 个代谢相关基因对（MRGPs）组成的预后标志物。进行 GSEA 和免疫亚型分析，以揭示 MRGP 风险组之间在生物学过程上的差异。单细胞 RNA-seq 数据集用于检查构成签名的每个 MRG 在肿瘤组织亚群中的表达分布。最后，在原位 GBM 模型中对 MRG 与肿瘤进展的关联进行了生物学验证。
代谢特征仍然是一个独立的预后因素（危险比，5.71 [3.542-9.218]，<0.001），可根据总体生存情况将患者分为高风险和低风险组，这在 MGMTp 甲基化状态、表达亚型和化疗/放疗治疗的亚组中具有显著差异。MRGP 风险组之间的免疫相关生物学过程存在显著差异。与低风险组相比，高风险组在体液免疫反应和吞噬过程中显著富集，并且单核细胞浸润更多，激活的 DC、NK 和 γδ T 细胞浸润更少。scRNA-seq 数据集分析确定，5 个 MRGs（ABCA1、HMOX1、MTHFD2、PIM1 和 PTPRE）在 TAMs 中的表达水平随代谢风险增加而增加。随着肿瘤进展，TAMs 中 ABCA1 的表达水平与肿瘤组织中 TAMs 的群体呈正相关。下调 ABCA1 水平可以促进 TAM 向炎症表型极化并控制肿瘤生长。
代谢特征有望用于原发性 IDH GBM 患者的个体化管理。
