代谢相关基因对特征分析确定肿瘤相关巨噬细胞上 ABCA1 表达水平是原发性 IDH(WT) 胶质母细胞瘤的预后生物标志物

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 WT ) and lack reliable signatures to identify distinct entities.

To develop a robust prognostic signature for IDH WT 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], P < 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 WT GBM patients.