TY - JOUR
T1 - T cells specific for α-myosin drive immunotherapy-related myocarditis
AU - Axelrod, Margaret L.
AU - Meijers, Wouter C.
AU - Screever, Elles M.
AU - Qin, Juan
AU - Carroll, Mary Grace
AU - Sun, Xiaopeng
AU - Tannous, Elie
AU - Zhang, Yueli
AU - Sugiura, Ayaka
AU - Taylor, Brandie C.
AU - Hanna, Ann
AU - Zhang, Shaoyi
AU - Amancherla, Kaushik
AU - Tai, Warren
AU - Wright, Jordan J.
AU - Wei, Spencer C.
AU - Opalenik, Susan R.
AU - Toren, Abigail L.
AU - Rathmell, Jeffrey C.
AU - Ferrell, P. Brent
AU - Phillips, Elizabeth J.
AU - Mallal, Simon
AU - Johnson, Douglas B.
AU - Allison, James P.
AU - Moslehi, Javid J.
AU - Balko, Justin M.
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/11/24
Y1 - 2022/11/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85141955793&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85141955793&partnerID=8YFLogxK
U2 - 10.1038/s41586-022-05432-3
DO - 10.1038/s41586-022-05432-3
M3 - Article
C2 - 36385524
AN - SCOPUS:85141955793
SN - 0028-0836
VL - 611
SP - 818
EP - 826
JO - Nature
JF - Nature
IS - 7937
ER -