Abstract
BackgroundImmunotherapy, especially checkpoint inhibitors targeting PD-1 or PD-L1, has revolutionized cancer therapy. However, PD-1/PD-L1 inhibitors have not been investigated thoroughly in glioblastoma (GBM). Studies have shown that polymerase 1 and transcript release factor (PTRF/Cavin-1) has an immune-suppressive function in GBM. Thus, the relationship between PTRF and PD-L1 and their role in immune suppression requires further investigation in GBM.MethodsWe used public databases and bioinformatics analysis to investigate the relationship between PTRF and PD-L1. We next confirmed the predicted relationship between PTRF and PD-L1 in primary GBM cell lines by using different experimental approaches. RIP-Seq, RIP, ChIP, and qRT-PCR were conducted to explore the molecular mechanism of PTRF in immunosuppression.ResultsWe found that PTRF stabilizes lncRNA NEAT1 to induce NF-κB and PD-L1 and promotes immune evasion in GBM. PTRF was found to correlate with immunosuppression in the public GBM databases. PTRF increased the level of PD-L1 in primary cell lines from GBM patients. We carried out RIP-Seq of GBM cells and found that PTRF interacts with lncRNA NEAT1 and stabilizes its mRNA. PTRF also promoted the activity of NF-κB by suppressing UBXN1 expression via NEAT1 and enhanced the transcription of PD-L1 through NF-κB activation. Finally, PTRF promoted immune evasion in GBM cells by regulating PD-1 binding and PD-L1 mediated T cell cytotoxicity.ConclusionsIn summary, our study identified the PTRF-NEAT1-PD-L1 axis as a novel immune therapeutic target in GBM.
Highlights
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults [1]
Further we found that PTRF interacts with long noncoding RNAs (lncRNAs) nuclear enriched abundant transcript 1 (NEAT1) and maintains the mRNA stability of NEAT1, increasing H3K27me3 level on the UBXN1 promoter, which results in the binding of NF-kB to the PD-L1 promoter
Real-time quantitative PCR (RT-qPCR) determined that the mRNA level of PD-L1 was increased in N9 PTRF and TBD0220 PTRF cells compared with the control cells (Figure 1E)
Summary
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults [1]. Standard treatment regimens, including surgery, temozolomide chemotherapy, and radiation therapy, fail to improve patient survival [2]. Immunotherapy, immune checkpoint blockade with anti-programmed death 1 (PD-1)/PD-1 ligand (PD-L1) antibodies, has radically changed the treatment of multiple tumors [3,4,5]. Clinical studies investigating the use of anti-PD-1/PD-L1 in GBM remain are limited [6]. Previous studies demonstrated that PD-L1 protein levels are associated with glioma grades, with elevated levels on tumor cells facilitating immune evasion in glioma patients [10, 11]. One possible mechanism of immune evasion in GBM is the upregulation of PD-L1 which requires an in-depth investigation. Studies have shown that polymerase 1 and transcript release factor (PTRF/Cavin-1) has an immune-suppressive function in GBM. The relationship between PTRF and PD-L1 and their role in immune suppression requires further investigation in GBM
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