1新光醫院 泌尿科、2新光醫院 中央研究室、3台北醫學大學 醫學院、4輔仁大學 醫學院
Cis-platinum induces immunity evasion through PD-L1 upregulation in bladder cancer cells
Thomas I-Sheng Hwang1,2,3,4, An-Chen Chnag2, Po-Chun Chen2, Shan-Che Yang2, Te-Fu Tsai 1, Hung-En Chen1, Yi-Chia Lin1,4, Kuang-Yu Chou1, and Ji-Fan Lin2
Department of Urology, Shin Kong Wu Ho-Su Memorial Hospital1, Central Laboratory, Shin Kong Wu Ho-Su Memorial Hospital2, Department of Urology, Taipei Medical University3, Division of Urology, School of Medicine, Fu-Jen Catholic University4, Taipei, Taiwan.
Chemotherapeutic drugs are now considered to exert anti-tumor effects, by inducing an immune response-evading ability in cancer cells. Cis-platinum has been used as a main therapeutic agent in advanced or metastatic bladder cancer (BC). Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have been broadly implicated in cancer immunotherapy, which improving overall outcomes. The underlying mechanism of cis-platinum in mediating PD-L1 expression is not fully understood especially the involvement of immunity evasion. In this study, the role of PD-L1 expression and immunity evasion after cis-platinum treatment was investigated.
Materials and methods:
The BC cell lines T24 and 5637 were treated with various concentrations of cis-platinum (0, 6.25, 12.5, and 25 μM) for 24 h. Western blot and quantitative real-time PCR (qPCR) were used to measure the levels of PD-L1 protein and mRNA expression, respectively. Calcein AM (1μM), a cell-permeant dye, was used to analyze natural killer (NK) cell-mediated cytotoxicity of BC cells.
In our in vitro experiments, we found that chemotherapeutic drug cis-platinum induced PD-L1 but not PD-L2 expression in BC cell lines T24 and 5637. Furthermore, the expression level of PD-L1 was increased in a dose- and time-dependent manner after cis-platinum treatment. We, therefore, increased in whether cis-platinum-induced PD-L1 in BC cells can evade the NK cell immune surveillance. The data showed that treatment of cells with cis-platinum inhibited the ability of NK cells to kill BC cells. Moreover, pretreatment of BC cells with anti-PD-L1 antibody (0.1 g/mL & 1g/mL) significantly induced NK cell-mediated cytotoxicity.
Cis-platinum may trigger immunity evasion of bladder cancer through PD-L1 up-regulation. This study suggests that the PD-L1 antibody should be used concomitantly with chemotherapy in the treatment of advanced and metastatic BC.