Modeling immune checkpoint inhibitor associated myocarditis in vitro and its therapeutic implications

Immune checkpoint inhibitor-associated myocarditis is the most lethal side effect of immune checkpoint blockade. Myocarditis leads to persistently increased mortality and lacks effective treatments. The development of patient-relevant disease models may enable disease prediction, increased understanding of disease pathophysiology, and the development of effective treatment strategies. Here, we report a new method to model immune checkpoint inhibitor-associated myocarditis <i>in vitro</i> via a co-culture of activated primary human immune cells, human induced pluripotent stem cell-derived cardiomyocytes, and FDA-approved immune checkpoint inhibitors to recapitulate myocarditis <i>in vitro.</i> Significant cardiomyocyte necrosis, arrhythmia development, and sarcomere destruction occur, replicating clinical findings from myocarditis. This tissue culture myocarditis phenotype may rely on an induced pluripotent stem cell-derived cardiomyocyte antigen-specific CD8⁺ T cell response. The administration of dexamethasone rescued cardiomyocyte viability, morphology, and electrophysiology and suppressed inflammatory cytokine production. In conclusion, we detail how this platform can effectively model and provide critical information about the morphological and electrophysiological changes induced by immune checkpoint inhibitor-associated myocarditis. We have also validated the ability of this platform to screen potential medications to treat immune checkpoint inhibitor-associated myocarditis. This work establishes a robust, scalable model for identifying new therapies and risk factors, which is valuable in delineating the nature of interactions between the immune system and the heart during myocarditis.