Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Cell Rep. 2022 Nov 8;41(6):111611. doi: 10.1016/j.celrep.2022.111611.
Immune checkpoint inhibitors (ICIs) are an effective therapy for various cancers; however, they can induce immune-related adverse events (irAEs) as a side effect. Myocarditis is an uncommon, but fatal, irAE caused after ICI treatments. Currently, the mechanism of ICI-associated myocarditis is unclear. Here, we show the development of myocarditis in A/J mice induced by anti-PD-1 monoclonal antibody (mAb) administration alone without tumor cell inoculation, immunization, or viral infection. Mice with myocarditis have increased cardiac infiltration, elevated cardiac troponin levels, and arrhythmia. Anti-PD-1 mAb treatment also causes irAEs in other organs. Autoimmune T cells recognizing cardiac myosin are activated and increased in mice with myocarditis. Notably, cardiac myosin-specific T cells are present in naive mice, showing a phenotype of antigen-experienced T cells. Collectively, we establish a clinically relevant mouse model for ICI-associated myocarditis and find a contribution of cardiac myosin-specific T cells to ICI-associated myocarditis development and pathogenesis.
免疫检查点抑制剂（ICIs）是各种癌症的有效治疗方法；然而，它们会引起免疫相关的不良反应（irAEs）作为副作用。心肌炎是一种罕见但致命的 irAE，发生在 ICI 治疗后。目前，ICI 相关心肌炎的机制尚不清楚。在这里，我们展示了在没有肿瘤细胞接种、免疫或病毒感染的情况下，单独使用抗 PD-1 单克隆抗体（mAb）给药在 A/J 小鼠中引发心肌炎的发展。患有心肌炎的小鼠心脏浸润增加，心肌肌钙蛋白水平升高，并出现心律失常。抗 PD-1 mAb 治疗还会导致其他器官的 irAEs。识别心肌肌球蛋白的自身免疫性 T 细胞被激活并在患有心肌炎的小鼠中增加。值得注意的是，心脏肌球蛋白特异性 T 细胞存在于未致敏的小鼠中，表现出抗原经验 T 细胞的表型。总之，我们建立了一种与临床相关的小鼠模型，用于研究 ICI 相关心肌炎，并发现心脏肌球蛋白特异性 T 细胞对 ICI 相关心肌炎的发展和发病机制有贡献。
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