PD-1/PD-L1 Signaling in Non-ICI Myocarditis

Immune checkpoint inhibitor (ICI)-mediated myocarditis is a notorious complication of cancer treatment; however, the role of immune checkpoints in the heart during inflammation remains unknown. We investigated myocardial expression of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) in non-ICI myocarditis. We performed a cross-species single-cell/-nucleus RNA sequencing comparative analysis, including 3 different models of myocarditis in mice and human hearts, with in vitro validation in human cells. This provided compelling evidence that PD-1/PD-L1 signaling in both murine and human non-ICI myocarditis is inherent to the myocardial inflammatory response. Specifically, cardiac endothelial cells and fibroblasts exhibited robust and sustained PD-L1 up-regulation in myocarditis, while also coinciding temporally with peak PD-1 expression on T cells, which presents an important defense mechanism. Therefore, immune checkpoints have global importance in myocarditis and may serve as a therapeutic target.