MiR-10b-5p Impairs TET2-Mediated Inhibition of PD-L1 Transcription Thus Promoting Immune Evasion and Tumor Progression in Glioblastoma

Abstract

Objective: Glioblastoma (GBM) is a highly aggressive primary brain tumor that shows intratumoral heterogeneity at the cellular and molecular level. Activation of programmed death receptor 1(PD-1) interaction with its ligand PD-L1 is a well-known mechanism requisite for immune evasion deployed by malignant tumors including GBM. Herein, we set out to dissect the mechanism explaining the regulation of PD-L1 gene expression in GBM. Methods:The clinical samples consisted of 37 GBM tissues and 18 normal brain tissues. GBM cell model was treated by microRNA (miRNA) inhibitor, DNA constructs, and siRNAs. Assays of CCK-8 and Transwell insert were employed to assess the survival, migratory and invasive ability of GBM cell model. The immunosuppressive factor production, T cell apoptosis, and T cell cytotoxicity to GBM cells were evaluated in the co-culture system.Results: GBM exhibited more miR-10b-5p abundance than normal at both tissue and cellular level. Suppression of miR-10b-5p weakened the ability of GBM cell model to survive, migrate, and invade, decreased the release of immunosuppressive factors, reduced T cell apoptosis, and strengthened the T cell cytotoxicity to GBM cell model. miR-10b-5p conferred a negative control of TET2 that was downregulated in GBM. The functions of miR-10b-5p on GBM cell aggressiveness and immune evasion were mediated by TET2. TET2 recruited histone deacetylases HDAC1 and HDAC2 into the PD-L1 promoter region thus inhibiting its transcription. Conclusion:The study demonstrated the importance of miR-10b-5p-mediated repression of TET2 in PD-L1-driven immune evasion and their potential for immunotherapeutic targeting in GBM.

Integrative analysis of genomic and epigenomic regulation reveals miRNA mediated tumor heterogeneity and immune evasion in lower grade glioma

“…9c ). This miRNA has been identified that impairs TET2-mediated PD-L1 transcription inhibition, by which to promote immune evasion and tumor progression in glioblastoma 51 . By further integration of the TIDE score correlated miRNAs and the putative targets obtained from public resources, we constructed a miRNA immune evasive network to describe the mechanism explaining roles of miRNA involved in immune envision regulation (Fig.…”

The Role of Non-Coding RNAs in Epigenetic Dysregulation in Glioblastoma Development

“…Analysis suggested that the possible underlying mechanism depends on the recruitment of histone deacetylases (HDAC1 and HDAC2) to PD-L1 promoter by TET2, as occupancy of the promoter site of these three enzymes was demonstrated. This study represents a valuable example that elucidates possible mechanisms of interconnections between multiple epigenetic components and their contribution to the overall cellular responding [51].…”

MicroRNAs as regulators of immune checkpoints in cancer immunotherapy: targeting PD-1/PD-L1 and CTLA-4 pathways

“…This suppression regulates TET2, which is downregulated in GBM, impacting the aggressiveness of GBM cells and their ability to evade the immune system. TET2 recruits HDAC1 and HDAC2 to the PD-L1 promoter, leading to the inhibition of PD-L1 transcription [ 152 ].…”