Wang Jin, Shi Fei, Shan Aijun
Department of Emergency, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China.
Front Oncol. 2022 Oct 6;12:946967. doi: 10.3389/fonc.2022.946967. eCollection 2022.
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.
诱导性共刺激分子（ICOS）是一种免疫共刺激分子，已发现在各种恶性肿瘤中发挥重要作用。本研究调查了ICOS在胶质瘤中的转录组谱和临床特征。从中国胶质瘤基因组图谱（CGGA）数据集下载了301例胶质瘤样本的临床信息和转录组数据进行分析（CGGA301队列）。此外，在来自TCGA胶质瘤数据集的697个具有RNAseq数据的样本和来自CGGA325数据集的325个具有RNAseq数据的胶质瘤中验证了结果。在组织微阵列（TMA）中进行免疫组织化学以评估不同WHO分级中ICOS蛋白的表达。此外，使用来自CGGA和GSE 163108数据集的单细胞测序数据来分析不同细胞类型中的ICOS表达。使用R语言进行统计分析和图形制作。我们发现ICOS在高级别、IDH野生型和间充质亚型的胶质瘤中显著上调。功能富集分析表明ICOS主要参与胶质瘤相关的免疫反应。此外，ICOS与其他免疫检查点密切相关，包括PD1/PD-L1/PD-L2途径、CTLA4、ICOSL（ICOS配体）和IDO1。随后的肿瘤免疫功能障碍和排除（TIDE）分析表明，ICOS表达较高的胶质母细胞瘤患者似乎对ICB治疗更敏感。此外，基于七个元基因簇，GSVA确定ICOS与HCK、LCK、MHC-I、MHC-II、STAT1和干扰素密切相关，尤其是与LCK，这表明ICOS与胶质瘤中的T细胞活性之间存在很强的相关性。在细胞谱系分析中，ICOS较高的胶质瘤倾向于将树突状细胞、单核细胞和巨噬细胞募集到肿瘤微环境中。单细胞测序分析表明ICOS在调节性T细胞（Tregs）中高表达，尤其是在成熟Tregs中。最后，ICOS较高的患者生存期缩短。ICOS是胶质瘤患者的独立预后因素。总之，较高的ICOS与胶质瘤的更多恶性程度相关，并且在胶质瘤相关的免疫反应中与Treg活性显著相关。此外，ICOS可作为胶质瘤的独立预后因素。我们的研究突出了ICOS在胶质瘤中的作用，并可能促进针对ICOS的胶质瘤治疗策略。
