PD-L1 confers glioblastoma multiforme malignancy via Ras binding and Ras/Erk/EMT activation

Abstract

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor due to the lack of effective therapeutic drugs. Cancer therapy targeting programmed cell death protein 1 (PD-1) or programmed death ligand-1 (PD-L1) is of revolutionary. However, the role of intrinsic PD-L1, which determines immune-therapy outcomes, remains largely unclear. Here we demonstrated an oncogenic role of PD-L1 via binding and activating Ras in GBM cells. RNA-sequencing transcriptome data revealed that PD-L1 significantly altered gene expression enriched in cell growth/migration/invasion pathways in human GBM cells. PD-L1 overexpression and knockout or knockdown demonstrated that PD-L1 promoted GBM cell proliferation and migration in vitro and in vivo. Mechanistically, PD-L1 prominently activated epithelial mesenchymal transition (EMT) process in a MEK/Erk- but not PI3K/Akt-dependent manner. Further, we identified intracellular interactions of PD-L1 and H-Ras, which led to Ras/Erk/EMT activation. Finally, we demonstrated that PD-L1 overexpression promoted while knockdown abolished GBM development and invasion in orthotopic GBM models of rodents. Taken together, we found that intracellular PD-L1 confers GBM cell malignancy and aggressiveness via binding Ras and activating the downstream Erk-EMT signaling. Thus, these results shed important insights in improving efficacy of immune therapy for GBM as well as other malignant tumors.

PKD3 promotes metastasis and growth of oral squamous cell carcinoma through positive feedback regulation with PD-L1 and activation of ERK -STAT1/3-EMT signaling

“…Based on data from the UALCAN database, UCSC Xena, and western blot, PKD3 and PD-L1 are significantly upregulated in OSCC. Previous studies showed that PD-L1 regulates EMT and promotes tumor growth and metastasis [23,26,[29][30][31][32][33]. Moreover, PD-L1 expression can be modulated by PKD3 [14].…”

“…Knockdown of PD-L1 could also affect the activation of ERK1/2 and STAT1/3. PD-L1 was previously shown to regulate the activation of ERK1/2 by binding with RAS, and consequently affect the EMT of tumor cells [33]. Additionally, the activation of STAT1/3 can be mediated by ERK1/2 [45][46][47][48][49][50][51].…”

Spred2 inhibits epithelial‑mesenchymal transition of colorectal cancer cells by impairing ERK signaling

“…Numerous studies have demonstrated that mitogen-activated protein kinase (MAPK)/ERK signaling participates in multiple cellular processes during tumor progression and metastasis, including growth, proliferation, differentiation and migration (7,8,(28)(29)(30). Notably, aberrant activation of MAPK/ERK signaling is always closely associated with the EMT of tumor cells in various cancers.…”

“…It has been widely demonstrated that aberrant activation of the Ras/Raf-1/extracellular-regulated kinase (ERK) signaling pathway plays pivotal roles in the initiation and progression of various tumors (7)(8)(9)(10). Spred2 is an important member of the sprouty-related EVH1 domain proteins, which are known to be negative regulators of growth factor-induced Ras/Raf-1/ERK activation (11,12).…”

Hyperprogression Under Immune Checkpoint-Based Immunotherapy—Current Understanding, The Role of PD-1/PD-L1 Tumour-Intrinsic Signalling, Future Directions and a Potential Large Animal Model

“…mRNA sequencing of PD-L1 high cells revealed activation of genes responsible for cell migration and motility. It was proposed that PD-L1 binds to Ras, then triggers the Ras/Raf/MAP/Erk cascade that regulates endothelial to mesenchymal transition, widely associated with enhanced tumorigenesis of GBM [82]. Besides effects on cancer intrinsic pathways, tumour PD-L1 expression was shown to protect tumour cells from IFN toxicity, which is a mechanism of antitumour immunity.…”