PD-L1 autoregulation promotes the proliferation, migration and invasion of glioblastoma cells via GP130/JAK2/STAT3/IRAK2/IL6 signaling pathway

Abstract

Glioblastoma (GBM) cells mediate immunosuppressive microenvironment, leading to poor response to programmed death-ligand 1(PD-L1) inhibitor therapy. How PD-L1 in GBM cells confers to GBM immunosuppressive microenvironment remains unclear. Here, we demonstrate that PD-L1 activated GP130/JAK2/STAT3/IRAK2/NFκB/IL6 pathway. We showed that PD-L1 was elevated in human primary GBM and promoted GBM cell viability, migration and invasion via activating janus kinase 2(JAK2) by interacting with glycoprotein 130(GP130) and PD-1 in GBM cells, leading to the activation of signal transducer and activator of transcription 3 (STAT3), a master that renders GBM immunosuppression. Overexpressing STAT3 reversed the effect of silencing PD-L1-mediated cell viability, proliferation, migration and invasion. STAT3 promoted interleukin-1 receptor-associated kinase 2(IRAK2) transcription. IRAK2 overexpression rescued the effect of silencing STAT3-mediated cell viability, proliferation, migration and invasion. Additionally, IRAK2 facilitated interleukin-6 (IL6) expression via activating nuclear factor kappa-B (NFκB). Our results indicate that PD-L1/GP130/JAK2/STAT3/IRAK2/NFκB/IL6 axis promotes GBM cell viability, proliferation, migration and invasion via interacting with GP130 and PD-1 in GBM cells. Additionally, STAT3 transcriptionally promoted PD-L1 expression, thus forming loops to lead to PD-L1 autoregulation. IL6 positively correlated with GBM-associated macrophages, myeloid-derived suppressor cells and the inhibition of dendritic cells. Our study suggests that PD-L1 autoregulation may create immunosuppressive GBM via activating GP130/JAK2/STAT3/IRAK2/IL-6 pathway.