Transcriptome and single-cell analysis reveal the contribution of immunosuppressive microenvironment for promoting glioblastoma progression

Abstract

Background and objectives: GBM patients frequently exhibit severe local and systemic immunosuppression, limiting the possible efficacy of immunotherapy strategies. The mechanism through which immunosuppression is established in GBM tumors is the key to successful personalized immunotherapies.

Methods: We divided GBM patients into subtypes according to the expression characteristics of the TME typing-related signature matrix. WGCNA analysis was used to get co-expressed gene modules. The expression activity of hub genes retrieved from co-expressed modules was validated in two single-cell datasets. Then, cell-cell interaction was calculated.

Results: Four subtypes were identified in the TCGA and CGGA RNA-seq datasets simultaneously, one of which was an immunosuppressive subtype rich in immunosuppressive factors with low lymphocyte infiltration and an IDH1 mutation. Three co-expressed gene modules related to the immunosuppressive subtype were identified. These three modules are associated with the inflammatory response, angiogenesis, hypoxia, and carbon metabolism, respectively. The genes of the inflammatory response were mainly related to myeloid cells, especially TAM, angiogenesis was related to blood vessels; hypoxia and glucose metabolism were related to tumors, TAM, and blood vessels. Moreover, there was enhanced interaction between tumor cells and TAM.

Discussion: This research successfully found the immunosuppressive subtype and the major cell types, signal pathways, and molecules involved in the formation of the immunosuppressive subtype and will provide new clues for the improvement of GBM personalized immunotherapy in the future.

Keywords: GBM; TAM; WGCNA; immunosuppression; immunotherapy; single-cell.