Modulation of PD-L1 Expression by Cisplatin and Gemcitabine in Bladder Cancer Cells

Bladder cancer (BC) incidence is rising globally, despite available treatment options, including tumor resection, systemic chemotherapy, and immune checkpoint inhibitors targeting PD-1/PD-L1. Gemcitabine and cisplatin are commonly combined as first-line systemic therapy, yet their effects on PD-L1 expression remain unclear. This study evaluated the effects of cisplatin and gemcitabine, alone and combined, on PD-L1 expression in a BC cell line, RT-4, and a normal epithelial cell line, ARPE-19. Cells were treated with IC20 doses of each drug, and PD-L1 expression was quantified by qRT-PCR after 48 hours. In ARPE-19 cells, cisplatin treatment induced a dose-dependent PD-L1 increase, peaking at a 59.6-fold elevation at higher doses (p < 0.001), while gemcitabine alone showed no effect. The combination of low-dose cisplatin and gemcitabine further elevated PD-L1 expression (25.2-fold, p < 0.05). In contrast, in RT-4 cells, low-dose cisplatin downregulated PD-L1, but higher doses resulted in a 61.3-fold increase (p < 0.05). Gemcitabine alone downregulated PD-L1 in RT-4 cells; however, the combined treatment produced a 99.4-fold upregulation (p < 0.001). These findings highlight dose- and cell type-specific effects of cisplatin and gemcitabine on PD-L1 regulation, with combination therapy notably upregulating PD-L1 in BC cells. This underscores the potential for integrating chemotherapy with immune checkpoint inhibitors to counteract chemotherapy-induced immune evasion in BC. Differential responses between normal and cancer cells emphasize the need for tumor-specific therapeutic approaches and further research on PD-L1 regulation to optimize immune checkpoint therapy.