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: 10545278
• 负责人: Han Zhu
• 金额: $ 16.63万
• 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/10545278
• 关键词: Acute; Adoptive Transfer; Advanced Malignant Neoplasm; Affect; Antibody Binding Sites; Antigen Targeting; Antigens; Arrhythmia; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Biological Assay; Blood; CCR5 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Cardiac; Cardiac Death; Cardiovascular system; Cell Separation; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Cessation of life; Clonal Expansion; Clone Cells; Computational algorithm; Cytometry; Cytotoxic T-Lymphocytes; Data; Disease; Drug Side Effects; Drug Targeting; Ensure; Epitopes; Funding; Genetic Transcription; Goals; Granzyme; Grouping; Heart; Heart failure; Histopathology; Homing; Immune; Immune checkpoint inhibitor; Immunological Models; In Vitro; Inflammation; Inflammatory; Interferon Type II; Knockout Mice; Knowledge; Laboratories; Life; Lymphocyte; Lymphocytic Infiltrate; Malignant Neoplasms; Mediating; Molecular; Molecular Profiling; Monoclonal Antibodies; Mus; Myocardial; Myocarditis; Myocardium; Onset of illness; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Phenotype; Physicians; Play; Population; Prevention; Proliferating; Proteins; RANTES; Reaction; Regulatory Pathway; Reporting; Role; Safety; Scientist; Signal Transduction; Small Interfering RNA; Spleen; T cell receptor repertoire sequencing; T cell therapy; T-Cell Activation; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Tissues; Toxic effect; Translations; Up-Regulation; Work; age group; attenuation; autocrine; candidate identification; checkpoint therapy; chemokine; cohort; cytokine; cytotoxic; cytotoxicity; effective therapy; effector T cell; experimental study; heart cell; in vivo; inhibitor; insight; knock-down; mouse model; myocardial damage; myocardial injury; neoplastic cell; new therapeutic target; novel; novel therapeutics; paracrine; perforin; programmed cell death ligand 1; programmed cell death protein 1; receptor; response; side effect; single-cell RNA sequencing; skills; small molecule; sudden cardiac death; time use; tumor

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.

项目总结/摘要 心肌炎，心脏的病理性炎症，是心脏性猝死的严重原因， 所有年龄段的患者。免疫检查点抑制剂（ICI）是针对细胞毒性T细胞的单克隆抗体， 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 释放对T细胞针对肿瘤细胞的细胞毒性的内在制动的治疗剂。虽然现在依赖于 在治疗许多晚期癌症时，爆发性心肌炎被报道为危及生命的副作用 这些药物，导致严重的心律失常，心力衰竭和死亡。根据组织病理学，急性 在心脏中发现淋巴细胞浸润，多条证据表明T细胞和抗原介导的 现象在这份提案中，朱博士在ICI心肌炎患者中的初步数据和一个生殖系PD-1 ICI心肌炎（MRL-Pdcd 1-/-）基因敲除小鼠模型显示了克隆扩增的 细胞毒性效应CD 8 + T细胞被认为在这种疾病中起关键作用，具有趋化因子的上调 RANTES（CCL 5）及其受体（CCR 5）。朱博士假设ICI心肌炎是由克隆性 心脏中细胞毒性效应CD 8 + T细胞的扩增，其发病机制通过来自CD 8 + T细胞的信号传导而增强 CCL 5，她的目标是使用单细胞RNA-seq/单细胞TCR测序和T细胞免疫印迹来验证这一假设。 过继转移实验（目的1），以及MRL-Pdcd 1-/-小鼠中CCR 5的离体/体内敲低 (Aim 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诱导的心肌炎中，这种抗原的特性仍然是难以捉摸的。了解致病抗原 这种疾病可能导致对T细胞介导的心肌损伤的新认识。在她的建议的第二部分， 博士Zhu假设ICI诱导的心肌炎是一种由心脏特异性自身免疫性疾病引起的自身免疫性疾病， 触发T细胞活化/克隆扩增的抗原，导致心肌炎症。在目标3中， 她将利用称为GLIPH（互补位淋巴细胞相互作用）的新型计算算法 热点），以确定候选致病抗原ICI心肌炎。朱博士的工作将为一个主要的 心脏炎症领域的知识空白，并确定罪魁祸首T细胞亚群和致病因素 ICI心肌炎和T细胞诱导的心肌损伤中的抗原。这项建议的完成将提供一个 为朱博士成功转型为独立的医学科学家研究免疫学提供了平台。 心脏炎症/毒性机制。