Wnt5b-induced PCP/JNK Activation Promotes PD-L1 Expression and the Malignant Phenotype of Non-small Cell Lung Cancer

Abstract Background: Wnt5b is noncanonical Wnt ligand, and programmed-death ligand 1 (PD-L1) is a targeted agent for immunotherapy, but the mechanism by which Wnt5b regulates PD-L1 expression in non-small cell lung cancer (NSCLC) is unclear. Methods: Wnt5b and PD-L1 expressions were detected in NSCLC specimens by immunohistochemistry. The interrelationship connecting Wnt5b with PD-L1 was verified using dual-luciferase assay, immunofluorescence, coimmunoprecipitation, western blot，real-time PCR and xenograft tumor model. Results: Wnt5b and PD-L1 expressions were positively correlated in NSCLC specimens. Five-year survival time in the group with their coexpression was significantly lower than that without coexpression. Under the effect of Wnt5b, Frizzled-3 (Fzd3) initiated Dishevellde-3 (Dvl-3) membrane recruitment via DEP domain by Dvl-3 phosphorylation, contributing to activate PCP/JNK signaling through the small GTPase Rac1, and then upregulate PD-L1 expression and promote the malignant phenotype of NSCLC in vivo and in vitro. After PD-L1 antibody treatment, Wnt5b induced tumor growth was inhibited significantly in xenograft tumor model. Conclusion: We demonstrate a new signal transduction pathway: Wnt5b initiates Dvl-3 membrane recruitment via DEP domain by Fzd3 so as to promote Rac1–PCP/JNK–PD-L1 pathway, which provides a potential target for clinical intervention and immunotherapy in lung cancer.