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

Margaret L. Axelrod, Wouter C. Meijers, Elles M. Screever, Juan Qin, Mary Grace Carroll, Xiaopeng Sun, Elie Tannous, Yueli Zhang, Ayaka Sugiura, Brandie C. Taylor, Ann Hanna, Shaoyi Zhang, Kaushik Amancherla, Warren Tai, Jordan J. Wright, Spencer C. Wei, Susan R. Opalenik, Abigail L. Toren, Jeffrey C. Rathmell, P. Brent Ferrell, Elizabeth J. Phillips, Simon Mallal, Douglas B. Johnson, James P. Allison, Javid J. Moslehi () and Justin M. Balko ()
Additional contact information
Margaret L. Axelrod: Vanderbilt University Medical Center
Wouter C. Meijers: Vanderbilt University Medical Center
Elles M. Screever: Vanderbilt University Medical Center
Juan Qin: Vanderbilt University Medical Center
Mary Grace Carroll: Vanderbilt University Medical Center
Xiaopeng Sun: Vanderbilt University Medical Center
Elie Tannous: Vanderbilt University Medical Center
Yueli Zhang: Vanderbilt University Medical Center
Ayaka Sugiura: Vanderbilt University Medical Center
Brandie C. Taylor: Vanderbilt University Medical Center
Ann Hanna: Vanderbilt University Medical Center
Shaoyi Zhang: University of California San Francisco
Kaushik Amancherla: Vanderbilt University Medical Center
Warren Tai: Vanderbilt University Medical Center
Jordan J. Wright: Vanderbilt University Medical Center
Spencer C. Wei: The University of Texas MD Anderson Cancer Center
Susan R. Opalenik: Vanderbilt University Medical Center
Abigail L. Toren: Vanderbilt University Medical Center
Jeffrey C. Rathmell: Vanderbilt University Medical Center
P. Brent Ferrell: Vanderbilt University Medical Center
Elizabeth J. Phillips: Vanderbilt University Medical Center
Simon Mallal: Vanderbilt University Medical Center
Douglas B. Johnson: Vanderbilt University Medical Center
James P. Allison: The University of Texas MD Anderson Cancer Center
Javid J. Moslehi: Vanderbilt University Medical Center
Justin M. Balko: Vanderbilt University Medical Center

Nature, 2022, vol. 611, issue 7937, 818-826

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-05432-3

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