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

• Published in: Nature (London) Vol. 611; no. 7937; pp. 818 - 826
• Main Authors: 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., Balko, Justin M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.11.2022; Nature Publishing Group
• Subjects: 13/106; 13/109; 13/31; 13/51; 14/34; 14/35; 38/47; 38/91; 631/250; 631/250/251; 631/67/580; 692/499; Adoptive transfer; Animals; Antibodies; Antigens; Autoantigens - immunology; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CTLA-4 Antigen - deficiency; CTLA-4 Antigen - genetics; CTLA-4 protein; Cytotoxicity; Depletion; Effector cells; Gene expression; Gene sequencing; Heart diseases; Humanities and Social Sciences; Immune checkpoint; Immune system; Immunotherapy; Immunotherapy - adverse effects; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Medical prognosis; Mice; multidisciplinary; Muscles; Musculoskeletal system; Myocarditis; Myocarditis - chemically induced; Myocarditis - etiology; Myocarditis - mortality; Myocarditis - pathology; Myosin; Pathogenesis; Peptides; Peripheral blood; Science; Science (multidisciplinary); Skeletal muscle; T cell receptors; Toxicity; Ventricular Myosins - immunology
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-05432-3

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 α-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 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. Cytotoxic CD8 + T cells specific for α-myosin are identified as pivotal players in myocarditis associated with immune checkpoint inhibitor anticancer therapies.