Epigenetically regulated lncRNAs dissect the intratumoural heterogeneity and facilitate immune evasion of glioblastomas

Abstract

Background: Glioblastomas are the most common and malignant central nervous system (CNS) tumors that occupied a highly heterogeneous tumor microenvironment (TIME). Long noncoding RNAs (lncRNAs), whose expression can be modified by DNA methylation, are emerging as critical regulators in the immune system. However, knowledge about the epigenetic changes in lncRNAs and their contribution to the immune heterogeneity of glioma is still lacking. Methods: In this study, we integrated paired methylome and transcriptome datasets of glioblastomas and identified 2 robust immune subtypes based on lncRNA methylation features. The immune characteristics of glioma subtypes were compared. Furthermore, immune-related lncRNAs were identified and their relationships with immune evasion were evaluated. Results: Glioma immunophenotypes exhibited distinct immune-related characteristics as well as clinical and epigenetic features. 149 epigenetically regulated (ER) lncRNAs were recognized that possessed inverse variation in epigenetic and transcriptional levels between glioma subtypes. Immune-related lncRNAs were further identified through the investigation of their correlation with immune cell infiltrations and immune-related pathways. In particular, the 'Hot' glioma subtype with higher immunoactivity while a worse survival outcome was found to character immune evasion features. We finally prioritized candidate ER lncRNAs associated with immune evasion markers and response to glioma immunotherapy. Among them, CD109-AS1 and LINC02447 were validated as novel immunoevasive biomarkers for glioma through in vitro experiments. Conclusion: In summary, our study systematically reveals the crosstalk among DNA methylation, lncRNA, and immune regulation in glioblastomas, and will facilitate the development of epigenetic immunotherapy approaches.

Integrative analysis of genomic and epigenomic regulation reveals miRNA mediated tumor heterogeneity and immune evasion in lower grade glioma

“…It is worth noting that a recent study based on integrated analysis of DNA methylome and transcriptome data of glioblastoma revealed robust immune subtypes based on lncRNA methylation features. The immune-hot tumor also exhibited immune evasion features and poor survival of the patients, which indicated non-coding RNAs could play essential roles for the immunoregulatory process in glioma 66 . By estimating the correlations with infiltrating immunocytes and immune pathway activities, we identified immune-related miRNAs that may have prognosis value for LGG patients with essential immune miRNAs were prioritized, many of them have been reported to be associated with immune regulation and cancer therapy from previous studies.…”