Single-cell analyses of checkpoint-inhibition-induced myocarditis: implications into mechanisms of severe immune-related adverse events

 

Nearly half of all cancer patients are eligible to receive treatment with immune checkpoint inhibitors (ICI). Thus, preventing, identifying and treating immune-related adverse events (irAEs) are urgent challenges. Myocarditis is an uncommon irAE, affecting <1% of ICI-treated patients, but has a mortality rate of nearly 50%. To study the mechanisms of ICI-myocarditis, we used a mouse model in which a combination of checkpoint gene KO causes premature death due to myocarditis. By flow cytometry, the myocardial immune infiltrate was primarily composed of CD8+ T cells and CD68+ macrophages, akin to subjects with ICI-associated myocarditis, and anti-CD8 depleting antibodies rescued survival. Single-cell RNA-seq of heart tissue identified highly activated, clonal CD8+ T cells. TCR sequencing also demonstrated highly clonal, but private, TCRs in affected mice. Computational analysis revealed high structural similarity in these TCRs, suggestive of similar antigen binding. TCR sequencing of two subjects who died with ICI-myocarditis also showed high clonality in the heart. Antigen discovery efforts are underway to yield new insights into the pathophysiology of this irAE. For Research Use Only. Not for use in diagnostic procedures.

 

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