Identification of Causal T-Cell Mechanisms in Immune Checkpoint Inhibitor Induced Myocarditis

免疫检查点抑制剂诱发心肌炎的 T 细胞机制鉴定

• 批准号: 10712007
• 负责人: Han Zhu
• 金额: $ 4.84万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712007
• 关键词: Acute; Advanced Malignant Neoplasm; Affect; Antibody Binding Sites; Antigens; Arrhythmia; Autoantigens; Autoimmune Diseases; CCR5 gene; CD8-Positive T-Lymphocytes; Cancer Patient; Cardiac; Cardiac Death; Cardiovascular system; Cells; Cessation of life; Clonal Expansion; Computational algorithm; Cytotoxic T-Lymphocytes; Data; Disease; Drug Side Effects; Ensure; Grouping; Heart; Heart failure; Histopathology; Immune; Immune checkpoint inhibitor; Immunological Models; Inflammation; Inflammatory; Knockout Mice; Knowledge; Life; Lymphocyte; Lymphocytic Infiltrate; Malignant Neoplasms; Mediating; Molecular; Monoclonal Antibodies; Mus; Myocardial; Myocarditis; Pathogenesis; Pathogenicity; Pathologic; Patients; Physicians; Play; Population; Prevention; RANTES; Reaction; Reporting; Role; Safety; Scientist; Signal Transduction; T cell receptor repertoire sequencing; T cell therapy; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Tissues; Toxic effect; Up-Regulation; Work; age group; candidate identification; checkpoint therapy; chemokine; cytotoxic; cytotoxicity; experimental study; in vivo; insight; knock-down; myocardial damage; myocardial injury; neoplastic cell; novel; programmed cell death ligand 1; programmed cell death protein 1; receptor; side effect; single-cell RNA sequencing; sudden cardiac death

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. In this proposal, Dr. Zhu’s preliminary data in ICI myocarditis patients and a germline PD-1 knockout mouse model of ICI myocarditis (MRL-Pdcd1-/-) demonstrates a population of clonally-expanded cytotoxic effector CD8+ T-cells thought to play a critical role in this disease, with upregulation of the chemokine RANTES (CCL5) and its receptor (CCR5). Dr. Zhu hypothesizes that ICI myocarditis is caused by the clonal expansion of cytotoxic effector CD8+ T-cells in the heart, whose pathogenesis is potentiated by signaling from CCL5, and she will aim to test this hypothesis using single-cell RNA-seq/single-cell TCR sequencing and T-cell adoptive transfer experiments (Aim 1), as well as and ex-vivo/in-vivo knockdown of CCR5 in MRL-Pdcd1-/- mice (Aim 2). 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 in T-cell mediated myocardial damage. In the second part of her proposal, Dr. Zhu hypothesizes that ICI-induced myocarditis is an autoimmune disorder caused by cardiac-specific auto- antigens that trigger the activation/clonal expansion of T-cells, leading to myocardial inflammation. In Aim 3, she will utilize the novel computational algorithm called GLIPH (Grouping Lymphocyte Interactions by Paratope Hotspots) to identify candidate pathogenic antigens in ICI myocarditis. Dr. Zhu’s work will bridge a major knowledge gap in the field of cardiac inflammation and identify culprit T-cell subsets and disease-causing antigens in ICI myocarditis and T-cell induced myocardial injury. The completion of this proposal will provide a platform for Dr. Zhu’s successful transition to an independent physician scientist investigating immune mechanisms in cardiac inflammation/toxicity.

项目摘要/摘要 心肌炎是心脏的病理性炎症，是导致心脏性猝死的严重原因。 所有年龄段的患者。免疫检查点抑制物(ICIS)是抗细胞毒性T细胞的单抗 抗原-4(CTLA-4)或程序性死亡-1(PD-1)/程序性死亡-1配体(PD-1L)作为新的肿瘤 治疗释放T细胞对肿瘤细胞的细胞毒性的内在刹车。尽管ICIS现在依赖于 在治疗许多晚期癌症时，暴发性心肌炎已被报道为威胁生命的副作用。 会导致严重的心律失常、心力衰竭和死亡。在组织病理学下，急性 在心脏中发现了淋巴细胞的渗透，多条证据表明是T细胞和抗原介导的 现象。在这项建议中，朱博士的初步数据显示，ICI心肌炎患者和PD-1胚系 ICI心肌炎基因敲除小鼠模型(MRL-Pdcd1-/-)显示克隆性扩增的种群 细胞毒效应CD8+T细胞被认为在本病中起关键作用，并上调趋化因子 RANTES(CCL5)及其受体(CCR5)。朱博士假设ICI心肌炎是由克隆性心肌炎引起的 细胞毒效应CD8+T细胞在心脏中的扩增，其发病机制被来自 CCL5，她的目标是使用单细胞RNA-seq/单细胞TCR测序和T细胞来验证这一假设 CCR5在MRL-Pdcd1-/-小鼠体内的过继转移实验(AIM 1)及体外/体内敲除 (目标2)。 尽管对患者心脏组织的T细胞克隆性分析表明存在心脏特异性抗原 在脑梗塞诱发的心肌炎中，这种抗原(S)的身份仍然难以捉摸。了解罪魁祸首抗原 这种疾病可能导致对T细胞介导的心肌损伤的新见解。在她的提案的第二部分， 朱博士假设ICI诱发的心肌炎是一种自身免疫性疾病，由心脏特异性自身抗体引起. 触发T细胞活化/克隆性扩张，导致心肌炎症的抗原。在《目标3》中， 她将使用一种名为Gliph(按Paratope分组淋巴细胞交互)的新计算算法 热点)以确定ICI心肌炎的候选致病抗原。朱博士的工作将架起一座重大 心脏炎症领域的知识差距以及确定罪魁祸首T细胞亚群和致病因素 ICI心肌炎和T细胞所致心肌损伤的抗原。这项提案的完成将提供一个 朱博士成功转型为研究免疫的独立内科科学家的平台 心脏炎症/毒性的机制。