CTLA4 Mediates Immunosuppersion in the Tumor Microenvironment via Macrophage Recruitment for Glioblastoma Immunotherapy

Background: CTLA4 has been widely reported to contribute to downregulation of immune responses to anti-tumor activity. Anti-CTLA4 provides a novel strategy to improve the outcome of cancer immunotherapy, but the role of CTLA4 needs to be addressed in glioblastoma (GBM). To investigate the role of CTLA4 in GBM, we analyzed the sequencing data of CTLA4 and evaluated its clinical prognostic value. Methods: 467 GBM cases were enrolled into this study from 4 cohorts. In their works, the Cancer Genome Atlas (TCGA) cohort was divided into training set and the Chinese Glioma Genome Atlas (CGGA) cohort, REMBRANDT, and GSE84465 cohorts were divided into validation set. Then, the role of CTLA4 in tumor microenvironment (TME) of GBM was comprehensively investigated. Findings: Significant differences exist in immunological characteristics between low and high CTLA4 expression groups. Mutation analysis found distinct genomic patterns associated with CTLA4 expression. Next, network analysis found the module named c1-1562 including CTLA4 correlated with over survival (OS) in GBM. We also developed a predictive model to calculate the risk score of every GBM case and the risk score was independently related to OS. Furthermore, expression of CTLA4 was positively related to the infiltration level and function of macrophage in GBM TME based on seven independent algorithms and single cell RNA-seq data. Interpretation: This study confirmed that CTLA4 plays an obviously key role in clinical, genomic, and TME status. This will contribute to stratifying clinical treatment and enhancing the efficiency of cancer immunotherapy. Funding Information: This project was supported by National Natural Science Foundation of China (No. 82071996, No. 81802483 and No. 82003075), the Beijing Municipal Health Commission of China (No. PXM2019_026280_000002), the Capital’s Funds for Health Improvement and Research (No. 2018-1-1071), and Beijing Hospitals Authority Youth Program (No. QML20190507) Declaration of Interests: The authors have declared that no competing interest exists. Ethics Approval Statement: The study was conducted in accordance with good clinical practice guidelines and the declaration of Helsinki, which has been approved by Capital Medical University Institutional Review Board.