Sesé Borja, Íñiguez-Muñoz Sandra, Ensenyat-Mendez Miquel, Llinàs-Arias Pere, Ramis Guillem, Orozco Javier I J, Fernández de Mattos Silvia, Villalonga Priam, Marzese Diego M
Institut d'Investigació Sanitària Illes Balears (IdISBa), Cancer Epigenetics Laboratory, Cancer Cell Biology Group, 07120 Palma, Illes Balears, Spain.
Institut d'Investigació Sanitària Illes Balears (IdISBa), Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Cancer Cell Biology Group, Universitat de les Illes Balears, 07122 Palma, Illes Balears, Spain.
Cancers (Basel). 2022 Apr 21;14(9):2070. doi: 10.3390/cancers14092070.
Glioma stem cells (GSCs) have self-renewal and tumor-initiating capacities involved in drug resistance and immune evasion mechanisms in glioblastoma (GBM).
Core-GSCs (c-GSCs) were identified by selecting cells co-expressing high levels of embryonic stem cell (ESC) markers from a single-cell RNA-seq patient-derived GBM dataset ( = 28). Induced c-GSCs (ic-GSCs) were generated by reprogramming GBM-derived cells (GBM-DCs) using induced pluripotent stem cell (iPSC) technology. The characterization of ic-GSCs and GBM-DCs was conducted by immunostaining, transcriptomic, and DNA methylation (DNAm) analysis.
We identified a GSC population (4.22% ± 0.59) exhibiting concurrent high expression of ESC markers and downregulation of immune-associated pathways, named c-GSCs. In vitro ic-GSCs presented high expression of ESC markers and downregulation of antigen presentation HLA proteins. Transcriptomic analysis revealed a strong agreement of enriched biological pathways between tumor c-GSCs and in vitro ic-GSCs ( = 0.71). Integration of our epigenomic profiling with 833 functional ENCODE epigenetic maps identifies increased DNA methylation on HLA genes' regulatory regions associated with polycomb repressive marks in a stem-like phenotype.
This study unravels glioblastoma immune-evasive mechanisms involving a c-GSC population. In addition, it provides a cellular model with paired gene expression, and DNA methylation maps to explore potential therapeutic complements for GBM immunotherapy.
胶质瘤干细胞（GSCs）具有自我更新和肿瘤起始能力，参与胶质母细胞瘤（GBM）的耐药和免疫逃逸机制。
通过从单细胞RNA测序患者来源的GBM数据集（n = 28）中选择共表达高水平胚胎干细胞（ESC）标志物的细胞来鉴定核心GSCs（c - GSCs）。使用诱导多能干细胞（iPSC）技术对GBM来源的细胞（GBM - DCs）进行重编程，生成诱导性c - GSCs（ic - GSCs）。通过免疫染色、转录组学和DNA甲基化（DNAm）分析对ic - GSCs和GBM - DCs进行表征。
我们鉴定出一个GSC群体（4.22% ± 0.59），其同时高表达ESC标志物并下调免疫相关途径，命名为c - GSCs。体外培养的ic - GSCs表现出ESC标志物的高表达和抗原呈递HLA蛋白的下调。转录组分析显示肿瘤c - GSCs和体外ic - GSCs之间富集的生物学途径有很强的一致性（r = 0.71）。将我们的表观基因组分析与833个功能性ENCODE表观遗传图谱整合，确定了与干细胞样表型中多梳抑制标记相关的HLA基因调控区域的DNA甲基化增加。
本研究揭示了涉及c - GSC群体的胶质母细胞瘤免疫逃逸机制。此外，它提供了一个具有配对基因表达和DNA甲基化图谱的细胞模型，以探索GBM免疫治疗的潜在治疗补充方法。
