Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer
Matthew D. Galsky, Xiangnan Guan, Deepali Rishipathak, Aaron S. Rapaport, Hesham M. Shehata, Romain Banchereau, Kobe Yuen, Eugene Varfolomeev, Ruozhen Hu, Chia-Jung Han, Haocheng Li, Yuxin Liang, Domagoj Vucic, Li Wang, Jun Zhu, Haocheng Yu, Rebecca H. Herbst, Emma Hajaj, Evgeny Kiner, Aristotelis Bamias, Maria De Santis, Ian D. Davis, José Ángel Arranz, Eiji Kikuchi, Sandrine Bernhard, Patrick Williams, Chooi Lee, Ira Mellman, Shomyseh Sanjabi, Robert E. Johnston, Peter C. Black, Enrique Grande, Sanjeev Mariathasan
Abstract
In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. In addition, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts 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 mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens.