PD-L1 promotes tumor growth and progression by activating WIP and β-catenin signaling pathways and predicts poor prognosis in lung cancer

PD-L1 is overexpressed in tumor cells and contributes to cancer immunoevasion. However, the role of the tumor cell-intrinsic PD-L1 in cancers remains unknown. Here we show that PD-L1 regulates lung cancer growth and progression by targeting the WIP and beta -catenin signaling. Overexpression of PD-L1 promotes tumor cell growth, migration and invasion in lung cancer cells, whereas PD-L1 knockdown has the opposite effects. We have also identified WIP as a new downstream target of PD-L1 in lung cancer. PD-L1 positively modulates the expression of WIP. Knockdown of WIP also inhibits cell viability and colony formation, whereas PD-L1 overexpression can reverse this inhibition effects. In addition, PD-L1 can upregulate beta -catenin by inhibiting its degradation through PI3K/Akt signaling pathway. Moreover, we show that in lung cancer cells beta -catenin can bind to the WIP promoter and activate its transcription, which can be promoted by PD-L1 overexpression. The in vivo experiments in a human lung cancer mouse model have also confirmed the PD-L1-mediated promotion of tumor growth and progression through activating the WIP and beta -catenin pathways. Furthermore, we demonstrate that PD-L1 expression is positively correlated with WIP in tumor tissues of human adenocarcinoma patients and the high expression of PD-L1 and WIP predicts poor prognosis. Collectively, our results provide new insights into understanding the pro-tumorigenic role of PD-L1 and its regulatory mechanism on WIP in lung cancer, and suggest that the PD-L1/Akt/beta -catenin/WIP signaling axis may be a potential therapeutic target for lung cancers.