T cells specific for a-myosin drive immunotherapy-related myocarditis

Article

关键词: LYMPHOCYTES;    EXPRESSION;    ALPHA;    HEART;    MICE;   

DOI  :  10.1038/s41586-022-05432-3

来源: SCIE

【 摘 要 】

Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy(1). The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1(-/-)Ctla4(+/-) mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration(2). Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1(-/-)Ctla4(+/-) mice, we identify clonal effector CD8(+) T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1(-/-)Ctla4(+/-) mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8+ T cells. The cardiac-specific protein a-myosin, which is absent from the thymus(3,4), was identified as the cognate antigen source for three major histocompatibility complex class I-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-MC were expanded by alpha-myosin peptides. Moreover, these alpha-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that alpha-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8(+) T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity.

【 授权许可】

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