Immunomodulatory effect of cisplatin and carboplatin in human and mouse cell line in vitro
The Phase 3 1L urothelial carcinoma (IMvigor130) trial revealed more favorable effects on overall survival with atezolizumab combined with gemcitabine and cisplatin (GemCis) than with atezolizumab combined with gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin vs carboplatin as a potential explanation for these clinical observations. GemCis compared with GemCarbo ± atezolizumab induced transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T-cell activation programs. In vitro experiments demonstrated that cisplatin, compared with carboplatin, exerted direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in urothelial carcinoma and highlight the potential importance of specific chemotherapy backbones for immune checkpoint blockade combination therapies. Overall design: To profile the impact of cisplatin and carboplatin on the whole transcriptomes of tumor cells, human bladder cancer cells (5637 and RT112) and murine colon cancer cells (MC38) were treated with cisplatin (5 µM), carboplatin (35 µM), or dimethyl sulfoxide control for 24 hours. In addition, we collected 5637 cells that had been treated for 24 hours with cisplatin (5 µM) or carboplatin (35 µM) in the presence or absence of an ATR inhibitor (1 µM) to evaluate the role of DNA damage sensor ATR in cisplatin- or carboplatin-mediated transcriptome changes.