Single‐cell RNA sequencing reveals the altered innate immunity in immune checkpoint inhibitor‐related myocarditis

Abstract Myocarditis has emerged as a rare but lethal immune checkpoint inhibitor (ICI)‐associated toxicity. However, the exact mechanism and the specific therapeutic targets remain underexplored. In this study, we aim to characterise the transcriptomic profiles based on single‐cell RNA sequencing from ICI‐related myocarditis. Peripheral blood mononuclear cell (PBMC) samples were collected from four groups for single‐cell RNA sequencing: (1) patients with newly diagnosed lung squamous cell carcinoma before treatment (Control Group); (2) patients with lung squamous cell carcinoma with PD‐1 inhibitor therapy who did not develop myocarditis (PD‐1 Group); (3) patients during fulminant ICI‐related myocarditis onset (Myocarditis Group); and (4) Patients with fulminant ICI‐related myocarditis during disease remission (Recovery Group). Subcluster determination, functional analysis, single‐cell trajectory and cell–cell interaction analysis were performed after scRNA‐seq. Bulk‐RNA sequencing was performed for further validation. Our results revealed the diversity of cellular populations in ICI‐related myocarditis, marked by their distinct transcriptional profiles and biological functions. Monocytes, NKs as well as B cells contribute to the regulation of innate immunity and inflammation in ICI‐related myocarditis. With integrated analysis of scRNA‐seq and bulk sequencing, we identified S100A protein family as a potential serum marker for ICI‐related myocarditis. Our study has created a cell atlas of PBMC during ICI‐related myocarditis, which would shed light on the pathophysiological mechanism and potential therapeutic targets of ICI‐related myocarditis in continuous exploration.