背景:聚集是一种溶酶体依赖性过程,它降解错误折叠的蛋白质缩合物以维持癌细胞稳态。尽管它在细胞蛋白质质量控制中很重要,聚集性吞噬在神经胶质瘤中的作用尚不清楚.
目的:研究神经胶质瘤和不同细胞类型的神经胶质瘤中聚集吞噬相关基因(ARGs)的表达,并开发基于ARGs的预后特征来预测预后,肿瘤微环境,和神经胶质瘤的免疫治疗反应。
方法:通过搜索Reactome数据库鉴定ARG。我们使用来自癌症基因组图谱(TCGA,n=669)通过Lasso-Cox回归。我们在临床亚组和CGGA队列中验证了签名的稳健性(n=970)。使用基因集富集分析(GSEA)来鉴定在ARPS亚组中富集的途径。还在单细胞水平上研究了ARG与巨噬细胞之间的相关性。
结果:共有44种ARGs在不同细胞类型的胶质瘤中表现出异质性表达。5个ARG(HSF1,DYNC1H1,DYNLL2,TUBB6,TUBA1C)被鉴定为发展ARPS,一个独立的预后因素。GSEA显示高ARPS患者的基因集大多富集在细胞周期,DNA复制,和免疫相关途径。高ARPS亚组免疫细胞浸润状态较高,特别是巨噬细胞,Treg细胞,和中性粒细胞。APRS与肿瘤突变负荷(TMB)和免疫治疗反应预测因子呈正相关。在单细胞水平,我们发现ARGs与巨噬细胞发育相关,并鉴定出ARGs介导的巨噬细胞亚型与肿瘤细胞具有明显的通讯特征.VIM+巨噬细胞被鉴定为促炎的并且与恶性细胞具有更高的相互作用。
结论:我们确定了一种基于ARGs预测神经胶质瘤预后的新特征,肿瘤微环境,和免疫疗法反应。我们强调神经胶质瘤中ARGs介导的巨噬细胞表现出经典特征。
BACKGROUND: Aggrephagy is a lysosome-dependent process that degrades misfolded protein condensates to maintain cancer cell homeostasis. Despite its importance in cellular protein quality control, the role of aggrephagy in glioma remains poorly understood.
OBJECTIVE: To investigate the expression of aggrephagy-related genes (ARGs) in glioma and in different cell types of gliomas and to develop an ARGs-based prognostic signature to predict the prognosis, tumor microenvironment, and immunotherapy response of gliomas.
METHODS: ARGs were identified by searching the Reactome database. We developed the ARGs-based prognostic signature (ARPS) using data from the Cancer Genome Atlas (TCGA, n = 669) by Lasso-Cox regression. We validated the robustness of the signature in clinical subgroups and CGGA cohorts (n = 970). Gene set enrichment analysis (GSEA) was used to identify the pathways enriched in ARPS subgroups. The correlations between ARGs and macrophages were also investigated at single cell level.
RESULTS: A total of 44 ARGs showed heterogeneous expression among different cell types of gliomas. Five ARGs (HSF1, DYNC1H1, DYNLL2, TUBB6, TUBA1C) were identified to develop ARPS, an independent prognostic factor. GSEA showed gene sets of patients with high-ARPS were mostly enriched in cell cycle, DNA replication, and immune-related pathways. High-ARPS subgroup had higher immune cell infiltration states, particularly macrophages, Treg cells, and neutrophils. APRS had positive association with tumor mutation burden (TMB) and immunotherapy response predictors. At the single cell level, we found ARGs correlated with macrophage development and identified ARGs-mediated macrophage subtypes with distinct communication characteristics with tumor cells. VIM+ macrophages were identified as pro-inflammatory and had higher interactions with malignant cells.
CONCLUSIONS: We identified a novel signature based on ARGs for predicting glioma prognosis, tumor microenvironment, and immunotherapy response. We highlight the ARGs-mediated macrophages in glioma exhibit classical features.