This study identified CXCR6+ T cells as key drivers of immune checkpoint inhibitor-associated myocarditis, particularly with combination ICI therapy including anti-LAG-3 agents. The mechanistic insight may guide future prevention and treatment strategies for this serious complication.
BACKGROUND:Myocarditis is a severe complication of immune checkpoint inhibitors (ICIs). The major risk factor for ICI myocarditis is the use of combination ICI treatment, especially when relatlimab, a novel anti–LAG-3 (lymphocyte-activation gene 3) antibody, is combined with anti–PD-1 (programmed cell death protein 1) therapy. Although pathogenic T cells are necessary for ICI myocarditis, the specific signaling and T-cell populations that drive cardiac infiltration have not been fully elucidated, especially in setting of anti–LAG-3/PD-1 treatment.METHODS:We used VigiBase, an international pharmacovigilance database, to assess the risk of myocarditis with anti–LAG-3 compared with other ICI treatment regimens. We identified a mouse model of LAG-3/PD-1–associated ICI myocarditis through genetic deletion of immune checkpoints LAG-3 and PD-1 (Lag3-/-, Pdcd1-/-mice) and performed rigorous cardiac phenotyping using histology, flow cytometry, electrocardiography, single-cell RNA sequencing, an
