BRD4 promotes immune escape of glioma cells by upregulating PD-L1 expression.

Purpose: Glioblastoma multiforme (GBM) poses significant challenges in treatment due to its aggressive nature and immune escape mechanisms. Despite recent advances in immune checkpoint blockade therapies, GBM prognosis remains poor. The role of bromodomain and extraterminal domain (BET) protein BRD4 in GBM, especially its interaction with immune checkpoints, is not well understood. Our study aimed to explore the role of BRD4 in GBM, especially the immune aspects.
Methods: In this study, we performed bioinformatics gene expression and survival analysis of BRD4 using TCGA and CGGA databases. In addition, we investigated the effects of BRD4 on glioma cell proliferation, invasion and migration by clone formation assay, Transwell assay, CCK8 assay and wound healing assay. Chromatin immunoprecipitation (ChIP) assay was conducted to confirm BRD4 binding to the programmed death ligand 1 (PD-L1) promoter. GL261 cells with BRD4 shRNA and/or PD-L1 cDNA were intracranially injected into mice to investigate tumor growth and survival time. Tumor tissue characteristics were analyzed using H&E and IHC staining and immune cell infiltration were assessed by flow cytometry.
Results: The results showed that elevated expression of BRD4 in high-grade gliomas was associated with poor patient survival. In addition, we validated the promotional effects of BRD4 on glioma cell proliferation, invasion and migration. The results of ChIP experiments showed that BRD4 is a regulator of PD-L1 at the transcriptional level, implying that it is involved in the immune escape mechanism of glioma cells. In vivo studies showed that BRD4 knockdown inhibited tumor growth and reduced immunosuppression, improving prognosis.
Conclusion: BRD4 has the capability to regulate the growth of glioblastoma and enhance immune suppression by promoting PD-L1 expression. Targeting BRD4 represents a promising direction for future research and treatment.
Competing Interests: Declarations. Ethics approval and consent to participate: Approval of the research protocol by an institutional review board: The research protocol was approved by the Institutional Review Board of the First Affiliated Hospital of Soochow University. Animal Studies: All animal procedures and experimental methods were approved by the Medical Ethics Committee of the First Affiliated Hospital of Soochow University. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)