PD-1/PD-L1 Interaction Upregulates YAP1 Expression in HepG2 Cells Through MAPK/ERK Pathway

Abstract

Background Antibodies, which target programmed cell death protein-1 (PD-1) or its ligand programmed death ligand-1 (PD-L1), can rescue T cells from an exhausted state and resume their immune response to cancer cells. Clinically, the purpose of blocking the PD-1/PD-L1 signaling pathway is to induce immune cells to play an anti-tumor role. However, the effect of intertumor PD-1/PD-L1 signal blocking on tumor cells remains unclear. Methods HepG2 cells were treated with DHA, IFN-γ, BSA, DDP, PD-1-Fc (1 μg/ml), IgG-Fc, nivolumab, or human IgG for 24 h, respectively. GEPIA, cBioPortal, and TIMER databases were used to analyze the correlation between YAP1, PD-1, and PD-L1 and ERK, ERK-5, JNK, and p38. Western blot was used to detect the expression of YAP1 and p-ERK. Results GEPIA, cBioPortal, and TIMER databases analysis showed that YAP1 was positively correlated with ERK. After HepG2 cells were treated with PD98059 (ERK inhibitor), the expression of YAP1 was decreased. In this study, we investigated the inhibitory effect of PD98059 on PD-1/PD-L1 signaling. Our study found that PD-1-Fc (PD-1 fusion protein) promoted the expression of p-ERK/ERK and YAP1 in HepG2 cells. In contrast, nivolumab (PD-1 blocking antibody) reduced the expression of p-ERK/ERK and YAP1 in IFN-γ-pretreated HepG2 cells. In addition, the application of DHA also inhibited the expression of p-ERK/ERK to inhibit YAP1. Furthermore, treatment of HepG2 cells with DHA alone or DHA combined with cisplatin (DDP) both inhibited the expression of p-ERK/ERK and YAP1. Conclusions These results suggested that PD-1/PD-L1 interactions between tumor cells could promote the expression of ERK or YAP1 within tumors. Moreover, the conduction of PD-1/PD-L1 could be reversed using ERK inhibitors.

The current status and future of PD-L1 in liver cancer

“…Studies have found that YAP1 inhibitors reduce the expression of PD-L1 in tumor tissues, promote the infiltration of CD8 T cells and CD4 T cells into tumor tissue ( 108 ), which disrupt the immunosuppressive microenvironment of cancer and improve the efficacy of HCC treatment ( 109 ). Interestingly, our research group also found that PD-1/PD-L1 interaction up-regulates YAP1 expression in HepG2 cells through the MAPK/ERK pathway ( 110 ). M2-polarized macrophages stimulated by IgA complex activated YAP/TAZ mediated signaling pathway, inducing cell activation and PD-L1 up-regulation in vitro ( 111 ).…”