Transcriptome profile and clinical characterization of ICOS expression in gliomas.

Abstract

Inducible co-stimulator (ICOS), an immune costimulatory molecule, has been found to play an essential role across various malignancies. This study investigated the transcriptome profile and clinical characterization of ICOS in gliomas. Clinical information and transcriptome data of 301 glioma samples were downloaded from the Chinese Glioma Genome Atlas (CGGA) dataset for analysis (CGGA301 cohort). Furthermore, the results were validated in 697 samples with RNAseq data from the TCGA glioma dataset and 325 gliomas with RNAseq data from the CGGA325 dataset. Immunohistochemistry was performed to evaluate ICOS protein expression across different WHO grades in a tissue microarray (TMA). In addition, single-cell sequencing data from CGGA and GSE 163108 datasets were used to analyze the ICOS expression across different cell types. Statistical analyses and figure production were performed with R-language. We found that ICOS was significantly upregulated in higher-grade, IDH wild type, and mesenchymal subtype of gliomas. Functional enrichment analyses revealed that ICOS was mainly involved in glioma-related immune response. Moreover, ICOS showed a robust correlation with other immune checkpoints, including the PD1/PD-L1/PD-L2 pathway, CTLA4, ICOSL (ICOS ligand), and IDO1. Subsequent Tumor Immune Dysfunction and Exclusion (TIDE) analysis revealed that GBM patients with higher ICOS expression seemed to be more sensitive to ICB therapy. Furthermore, based on seven clusters of metagenes, GSVA identified that ICOS was tightly associated with HCK, LCK, MHC-I, MHC-II, STAT1, and interferon, especially with LCK, suggesting a strong correlation between ICOS and T-cell activity in gliomas. In cell lineage analysis, Higher-ICOS gliomas tended to recruit dendritic cells, monocytes, and macrophages into the tumor microenvironment. Single-cell sequencing analysis indicated that ICOS was highly expressed by regulatory T cells (Tregs), especially in mature Tregs. Finally, patients with higher ICOS had shortened survival. ICOS was an independent prognosticator for glioma patients. In conclusion, higher ICOS is correlated with more malignancy of gliomas and is significantly associated with Treg activity among glioma-related immune responses. Moreover, ICOS could contribute as an independent prognostic factor for gliomas. Our study highlights the role of ICOS in glioma and may facilitate therapeutic strategies targeting ICOS for glioma.