Cardiac myosin-specific autoimmune T cells contribute to immune-checkpoint-inhibitor-associated myocarditis

Immune checkpoint inhibitors (ICIs) are an effective therapy for various cancers; however, they can induce immune-related adverse events (irAEs) as a side effect. Myocarditis is an uncommon, but fatal, irAE caused after ICI treatments. Currently, the mechanism of ICI-associated myocarditis is unclear. Here, we show the development of myocarditis in A/J mice induced by anti-PD-1 monoclonal antibody (mAb) administration alone without tumor cell inoculation, immunization, or viral infection. Mice with myocarditis have increased cardiac infiltration, elevated cardiac troponin levels, and arrhythmia. Anti-PD-1 mAb treatment also causes irAEs in other organs. Autoimmune T cells recognizing cardiac myosin are activated and increased in mice with myocarditis. Notably, cardiac myosin-specific T cells are present in naive mice, showing a phenotype of antigen-experienced T cells. Collectively, we establish a clinically relevant mouse model for ICI-associated myocarditis and find a contribution of cardiac myosin-specific T cells to ICI-associated myocarditis development and pathogenesis. [Display omitted] •PD-1 inhibitor treatment alone causes myocarditis development in A/J mice•Cardiac-myosin-specific T cells drive PD-1 inhibitor-induced myocarditis in mice•Cardiac-myosin-specific autoimmune T cells are present in naive mouse hearts•Cardiac-myosin-specific autoimmune T cells express PD-1 during naive conditions Won et al. demonstrate that PD-1 inhibitor treatment alone induces myocarditis in A/J mice, creating a mouse model for immune-checkpoint-inhibitor-associated myocarditis. Cardiac myosin-specific autoreactive T cells drive the pathogenesis of PD-1 inhibitor-induced myocarditis in mice. PD-1-expressing cardiac myosin-specific T cells are present in the heart during naive conditions.