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，心脏的病理炎症是心脏突然死亡影响的严重原因 所有年龄段的患者。免疫检查点抑制剂（ICI）是对细胞毒性T细胞的单克隆抗体 Antigen-4（CTLA-4）或程序性死亡-1（PD-1）/编程死亡-1配体（PD-1L）用作新型癌症 释放针对肿瘤细胞的T细胞细胞毒性的固有制动器的治疗剂。虽然ICI现已退休 为了治疗许多晚期癌症，据报道，暴发性心肌炎是威胁生命的副作用 在这些药物中，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 淋巴细胞浸润在心脏中发现，多行证据指向T细胞和抗原介导的 现象。在此提案中，朱博士在ICI心肌炎患者和生殖线PD-1中的初步数据 ICI心肌炎的基因敲除小鼠模型（MRL-PDCD1 - / - ）证明了克隆膨胀的种群 细胞毒性效应子CD8+ T细胞被认为在这种疾病中起着至关重要的作用，并上调趋化因子 Rantes（CCL5）及其受体（CCR5）。朱博士假设ICI心肌炎是由克隆引起的 心脏中细胞毒性效应子CD8+ T细胞的扩展，其发病机理通过信号传导潜在 CCL5，她的目标是使用单细胞RNA-seq/单细胞TCR测序和T细胞检验该假设 MRL-PDCD1 - / - 小鼠中CCR5的收养转移实验（AIM 1）以及和ex-Vivo/Vivo敲低 （目标2）。 尽管对患者心脏组织的T细胞克隆分析表明存在心脏特异性抗原 在ICI引起的心肌炎中，这种抗原的身份仍然难以捉摸。了解罪魁祸首 这种疾病可能导致对T细胞介导的心肌损伤的新见解。在她提议的第二部分中， 朱博士假设ICI诱发的心肌炎是由心脏特异性自身 - 触发T细胞激活/克隆膨胀的抗原，导致心肌注射。在AIM 3中， 她将利用称为gliph的新型计算算法（将淋巴细胞相互作用分组 热点）鉴定ICI心肌炎中候选病原抗原。朱博士的工作将桥梁 心脏感染领域的知识差距，并确定罪魁祸首T细胞亚群和引起疾病 ICI心肌炎和T细胞中的抗原诱导心肌损伤。该提案的完成将提供 朱博士成功过渡到独立物理科学家的平台，调查免疫 心脏感染/毒性的机制。