Immune checkpoint inhibitor–induced myocarditis is dependent on CD8 T cell–derived TNF and TNFR2 signaling

Immune checkpoint inhibition (ICI) has significantly advanced cancer treatment but is associated with immune-related adverse outcomes including lethal myocarditis. T cells against select cardiac antigens have emerged as a cause of myocarditis, yet the mechanisms by which these cells exert pathological effects remain unclear. To investigate the pathogenesis of ICI-induced myocarditis, we developed a mouse model with cardiac-restricted expression of the model antigen ovalbumin (Ova). Immunotherapy with antibodies against cytotoxic T cell antigen-4 (αCTLA-4) and programmed death-1 (αPD-1) uniquely drove the expansion of transferred Ova-specific naïve CD8 T cells and infiltration in the heart. The goal of this study was to identify pathways induced in immune cells interacting with pathogenic T cells. Here, Ova-specific CD8 T cells initiated innate immune activation, resulting in arrhythmias and lethal cardiomyopathy. The innate inflammation and cardiac damage were largely driven by T cell-derived tumor necrosis factor (TNF), as shown by the marked reduction of myocarditis in mice receiving TNF-deficient Ova-specific CD8 T cells or treated with tumor necrosis factor receptor 2 (TNFR2)-blocking antibody. Furthermore, targeting T cell-mediated innate inflammation via the TNF:TNFR2 axis ameliorated myocarditis while preserving the antitumor efficacy of immune checkpoint inhibitor (ICI) therapy. These findings clarify roles for the inhibitory receptors PD-1 and CTLA-4 in regulating self-reactive T cells and offer a clinically actionable path for protection from ICI-induced myocarditis while maintaining antitumor immunity.