1. T cells specific for α-myosin drive immunotherapy-related myocarditis
- Author
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Axelrod, Margaret L, Meijers, Wouter C, Screever, Elles M, Qin, Juan, Carroll, Mary Grace, Sun, Xiaopeng, Tannous, Elie, Zhang, Yueli, Sugiura, Ayaka, Taylor, Brandie C, Hanna, Ann, Zhang, Shaoyi, Amancherla, Kaushik, Tai, Warren, Wright, Jordan J, Wei, Spencer C, Opalenik, Susan R, Toren, Abigail L, Rathmell, Jeffrey C, Ferrell, P Brent, Phillips, Elizabeth J, Mallal, Simon, Johnson, Douglas B, Allison, James P, Moslehi, Javid J, and Balko, Justin M
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cardiovascular ,Heart Disease ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Animals ,Mice ,Autoantigens ,CD8-Positive T-Lymphocytes ,CTLA-4 Antigen ,Immunotherapy ,Myocarditis ,Ventricular Myosins ,General Science & Technology - Abstract
Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy1. The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1-/-Ctla4+/- mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration2. 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 α-myosin, which is absent from the thymus3,4, 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 α-myosin peptides. Moreover, these α-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that α-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.
- Published
- 2022