美国范德比尔特大学Justin M. Balko等研究人员合作发现，针对α-肌球蛋白的特异性T细胞驱动免疫疗法相关的心肌炎。相关论文于2022年11月16日在线发表在《自然》杂志上。

研究人员利用单细胞RNA和T细胞受体（TCR）测序对Pcdd1^-/-Ctla4^+/-小鼠的心脏免疫浸润进行分析，确定了克隆效应CD8⁺T细胞是主要的细胞群。用抗CD8耗竭性抗体治疗，而非抗CD4耗竭性抗体，可以改善Pdcd1^-/-Ctla4^+/-小鼠的生存。采纳来自心肌炎小鼠的免疫细胞会诱导受体的致命性心肌炎，这需要CD8⁺T细胞。心肌特异性蛋白α-肌球蛋白在胸腺中是不存在的，被确定为来自暴发性心肌炎小鼠的三个主要组织相容性复合体I类限制性TCR的认知抗原来源。三名免疫检查点抑制剂相关心肌炎（ICI-MC）患者的外周血T细胞被α-肌球蛋白肽扩增。此外，这些α-肌球蛋白扩增的T细胞与患病的心脏和骨骼肌共享TCR克隆型，这表明α-肌球蛋白可能是ICI-MC中一个重要的自身抗原。

这些研究强调了细胞毒性CD8⁺T细胞的关键作用，确定了ICI-MC中的一个候选自身抗原，并对ICI毒性的发病机制有了新的认识。

据介绍，免疫相关的不良事件，特别是严重的毒性，如心肌炎，是免疫检查点抑制剂在抗癌治疗中的主要挑战。ICI-MC的发病机制还不甚明了。Pdcd1^-/-/Ctla4^+/-小鼠再现了ICI-MC的临床病理特征，包括心肌T细胞浸润。

附：英文原文

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

Author: 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.

Issue&Volume: 2022-11-16

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 Tcell infiltration2. Here, using single-cell RNA and Tcell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1–/–Ctla4+/– mice, we identify clonal effector CD8+ Tcells 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+ Tcells. 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 classI-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood Tcells from three patients with ICI-MC were expanded by α-myosin peptides. Moreover, these α-myosin-expanded Tcells 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+ Tcells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity.

DOI: 10.1038/s41586-022-05432-3

Source: https://www.nature.com/articles/s41586-022-05432-3