Cisplatin contributes to programmed death-ligand 1 expression in bladder cancer through ERK1/2-AP-1 signaling pathway.

Te-Fu Tsai,Chao-Yen Ho,Po-Chun Chen,Thomas I-Sheng Hwang,Yi-Chia Lin,Kuang-Yu Chou,Ji-Fan Lin,Hung-En Chen

doi:10.1042/bsr20190362

Abstract

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 BC. Programmed cell death ligand-1 (PD-L1) is an important target for immunotherapy. It is known that PD-L1 is overexpressed in BC; a clinical trial involving PD-L1 immune checkpoint inhibitors in advanced BC 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 activator protein-1 (AP-1) to regulate PD-L1 expression. The chemotherapy drug such as cisplatin may trigger resistance of BC through PD-L1 up-regulation. The present study suggests that PD-L1 antibody should be used concomitantly with chemotherapy in the setting of advanced and metastatic BC.

Highlights

Bladder cancer (BC) is a commonly diagnosed urological malignancy with a very high recurrence rate
Since programmed cell death 1 (PD-1)/Programmed cell death ligand-1 (PD-L1) expression is the main indication for these immune checkpoint inhibitors, and the expression of these immune checkpoint proteins is up-regulated with the progression of BC, it is reasonable to hypothesize that PD-L1 overexpression may be involved in the progression of BC by providing an escape route for tumor cells to evade immune detection
Our results found that cisplatin dose-dependently promoted PD-L1 mRNA expression but not that of PD-L2, in BC-derived cell lines (Figure 1A,B)

Summary

Introduction

Bladder cancer (BC) is a commonly diagnosed urological malignancy with a very high recurrence rate. We show that PD-L1 expression in BC cells is up-regulated after cisplatin treatment and that this is mediated mainly by ERK1/2/ activator protein-1 (AP-1) signal transduction. Cisplatin treatment contributes to PD-L1 expression in BC-derived cell lines Our results found that cisplatin dose-dependently promoted PD-L1 mRNA expression but not that of PD-L2 (another ligand for PD-1), in BC-derived cell lines (Figure 1A,B).

Results

Conclusion