PD-L1 Confers Glioblastoma Multiforme Malignancy And Its Underlying Mechanism

Glioblastoma multiforme(GBM)is the most aggressive primary brain tumor,with poor prognosis due to the lack of effective therapeutic drugs.Programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)are novel discovered immune-inhibitory checkpoint molecules.Cancer therapy targeting programmed cell death protein 1(PD-1)/programmed death ligand-1(PD-L1)is of revolutionary.PD-1 exists mainly on cytotoxic T lymphocytes and PD-L1 is widely expressed on tumor cells.The binding of PD-L1 to PD-1 induces apoptosis/ exhaustion of cytotoxic T lymphocytes,resulting in the escape of cancer cells from immune surveillance.Recently,it was reported that tumor PD-L1 played roles in promoting tumor malignancy via modulating signaling pathway.But the role of PD-L1 in GBM malignancy is still unknown.Here we demonstrated an oncogenic role of PD-L1 in GBM via binding and activating Ras.In vitro studies demonstrated: 1.RNA-sequencing transcriptome data and enrichment analysis revealed that PD-L1 significantly altered gene expression enriched in cell growth/migration/invasion associated items in human GBM cells;2.PD-L1 overexpression promoted GBM cell proliferation and migration;3.PD-L1 knockout/knockdown inhibited GBM cell proliferation and migration;4.PD-L1 prominently activated epithelial mesenchymal transition(EMT)/proliferation/migration/invasion process in a MEK/Erk-dependent manner;4.PD-L1 interacted with H-Ras and increased the level of GTP-bound H-Ras.In vivo studies demonstrated: 1.PD-L1 knockdown abolished GBM development in nude mice;2.PD-L1 overexpression promoted GBM development and invasion in orthotopic GBM models of rats;3.PD-L1 overexpression promoted the EMT process in orthotopic glioma;4.Vimentin expression was significantly co-localized and correlated with PD-L1 signals in both C6/PD-L1 glioma and human GBM tissues.Taken together,we demonstrated that intracellular PD-L1 confers GBM cell malignancy and aggressiveness via binding Ras and activating the downstream MEKErk-EMT signaling.Thus,these results shed important insights in improving efficacy of immune therapy for GBM as well as other malignant tumors.