Identification of Causal Antigens in Immune Checkpoint Inhibitor-Induced Myocarditis

项目总结/摘要 心肌炎，心脏的病理性炎症，是影响所有年龄段患者的心脏性猝死的严重原因 组免疫检查点抑制剂（ICI）是针对细胞毒性T细胞抗原-4（CTLA-4）或 程序性死亡-1（PD-1）/程序性死亡-1配体（PD-1 L）用作新的癌症治疗剂以释放内源性 阻止了T细胞对肿瘤细胞的细胞毒性。尽管现在依赖于ICI来治疗许多晚期癌症， 据报道，暴发性心肌炎是这些药物的一种危及生命的副作用，可导致严重的心律失常、心脏病、 失败和死亡。根据组织病理学，在心脏中发现急性淋巴细胞浸润， 指向T细胞和抗原介导的现象。尽管患者心脏组织的T细胞克隆分析表明， 尽管ICI诱导的心肌炎中存在心脏特异性抗原，但这种抗原的身份仍然难以捉摸。 了解这种疾病的罪魁祸首抗原可能会导致对T细胞介导的免疫调节机制的新见解。 心肌损伤我假设ICI诱导的心肌炎是一种自身免疫性疾病，由心脏特异性自身免疫性疾病引起。 触发T细胞活化和克隆扩增的抗原，导致心肌炎症。这个目标 研究是使用一种称为CyTOF的先进免疫表型技术来表征T细胞亚群，然后 使用单细胞T细胞受体测序和一种名为GLIPH的新型计算算法（GLIPH）， 通过互补位热点的淋巴细胞相互作用），以鉴定负责ICI中T细胞活化的特异性表位。 诱发小鼠和人类心肌损伤。通过完成这个项目，我将揭示关键的见解， ICI诱导的心肌炎的生物学机制，这将弥合关于T细胞在 介导心肌损伤。我的研究结果将回答一个关键问题，即哪些免疫细胞类型在免疫系统中起主导作用。 ICI诱导的心肌炎，以及确定引起心脏毒性的致病抗原。越来越多的证据 表明免疫介导的心脏损伤可能是许多主要心血管疾病的核心， 自身免疫性心肌炎心力衰竭动脉粥样硬化作为一名物理学家兼科学家，我的长期目标是阐明 心脏病理性炎症的机制，以帮助治愈心血管疾病，并成为该领域的领导者 心脏炎症

Project Summary/Abstract Myocarditis, pathologic inflammation of the heart, is a serious cause of sudden cardiac death affecting patients of all age groups. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies to cytotoxic T-cell antigen-4 (CTLA-4) or programmed death-1 (PD-1)/programmed death-1 ligand (PD-1L) used as novel cancer therapeutics to release intrinsic brakes on T-cell cytotoxicity against tumor cells. Although ICIs are now relied upon to treat many advanced cancers, fulminant myocarditis has been reported as a life-threatening side effect of these drugs, leading to severe arrhythmias, heart failure and death. Under histopathology, an acute lymphocytic infiltrate is found in the heart, and multiple lines of evidence point to a T-cell and antigen-mediated phenomenon. Although T-cell clonal analysis of patient heart tissues suggest the existence of a cardiac-specific antigen in ICI-induced myocarditis, the identity of such antigen(s) remains elusive. Understanding the culprit antigens in this disease may lead to novel insights on the mechanism of T-cell mediated myocardial damage. I hypothesize that ICI-induced myocarditis is an autoimmune disorder caused by cardiac-specific auto- antigens that trigger the activation and clonal expansion of T-cells, leading to myocardial inflammation. The goal of this study is to use an advanced immunophenotyping technique called CyTOF to characterize T-cell subsets, and then use single-cell T-cell receptor sequencing and a novel computational algorithm called GLIPH (Grouping Lymphocyte Interactions by Paratope Hotspots) to identify specific epitopes responsible for T-cell activation in ICI- induced myocardial damage in mice and humans. By completing this project, I will uncover key insights into the biological mechanism of ICI-induced myocarditis which will bridge a major knowledge gap regarding the role of T-cells in mediating myocardial damage. My results will answer the key question of which immune cell types play a dominant role in ICI-induced myocarditis, as well as identify disease-causing antigens causing cardiotoxicity. There is increasing evidence to suggest that immune-mediated cardiac damage may be at the heart of many major cardiovascular diseases, ranging from autoimmune myocarditis to heart failure to atherosclerosis. My long-term goal as a physician-scientist is to elucidate mechanisms of pathological inflammation in the heart to help cure cardiovascular disease and become a leader in the field of cardiac inflammation.