Cisplatin contributes to programmed death-ligand 1 (PD-L1) expression in bladder cancer through ERK1/2 - AP-1 signaling pathway

Bladder cancer (BC) is the second most common urologic malignancy and the ninth most common malignancy worldwide. Surgical resection is the mainstay of treatment for patients with early-stage disease, whereas therapeutic options are limited for patients with advanced-stage or residual bladder cancer. Programmed cell death ligand-1 (PD-L1) is an important target for immunotherapy. It is known that PD-L1 is overexpressed in bladder cancer; a clinical trial involving PD-L1 immune checkpoint inhibitors in advanced bladder cancer is ongoing. In the present study, we used Western blot and quantitative real-time PCR (qPCR) to define the expression level of PD-L1 after cisplatin treatment in BC-derived cell lines. The signal activation was also evaluated by Western blot in BC-derived cell lines. We found that chemotherapeutic drug cisplatin can induce PD-L1 but not PD-L2 expression in BC-derived cell lines. Furthermore, the expression level of PD-L1 was increased in a dose- and time- dependent manner after cisplatin treatment. The cisplatin-induced PD-L1 expression is mainly mediated by ERK1/2 but not Akt/mTOR signal pathway. Moreover, we found that cisplatin activates transcription factor AP-1 to regulate PD-L1 expression. The chemotherapy drug such as cis-platinum may trigger resistance of bladder cancer through PD-L1 up-regulation. This study suggests that PD-L1 antibody should be used concomitantly with chemotherapy in the setting of advanced and metastatic bladder cancer.