Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Nature (London), 2022-11, Vol.611 (7937), p.818-826

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.