A single-cell transcriptomic atlas characterizes molecular features in ureteritis/cystitis induced by immune checkpoint inhibitors

Abstract

Abstract Common immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) include dermatological, gastrointestinal, pulmonary, or endocrine side effects. Although less common than other IrAEs, IrAEs involving the urinary tract and bladder are gradually being recognized by clinicians. However, the early diagnosis and optimal management of ICI-induced ureteritis/cystitis are challenging because the underlying mechanisms remain poorly understood. Here we report the results from a comprehensive single-cell analysis of cell populations implicated in ureteritis/cystitis induced by an anti-programmed-death-1 monoclonal antibody. We observed a striking expansion of T cells with highly cytotoxic state in the ureteritis/cystitis tissue, which was accompanied by a significant decrease in epithelial cell numbers. The proportion of macrophages was also increased in the ureteritis/cystitis tissue, compared with healthy tissue. Moreover, we identified changes in the molecular features of the CXCL, TNF, NF-κB, ITGB2, and GZMB signaling pathways. Collectively, our findings provide insights into the molecular mechanisms underlying ICI-induced ureteritis/cystitis and imply that modulating T cell, macrophage, epithelial cell, and endothelial cell functions by interfering with the identified signaling pathways could help guide new therapeutic strategies.