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: 10351289
• 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/10351289
• 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; 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; Interferons; Knockout Mice; Knowledge; Laboratories; Lead; 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; 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; 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.

项目概要/摘要 心肌炎是心脏的病理性炎症，是导致心源性猝死的严重原因，影响 免疫检查点抑制剂 (ICIs) 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-1L) 用作新型癌症 尽管现在依赖 ICI，但仍需要一些疗法来释放 T 细胞对肿瘤细胞的细胞毒性的内在制动。 据报道，在治疗许多晚期癌症时，暴发性心肌炎会产生危及生命的副作用 根据组织病理学，这些药物会导致严重的心律失常、心力衰竭和死亡。 心脏中发现淋巴细胞浸润，多种证据表明 T 细胞和抗原介导的 在这个提议中，朱博士在ICI心肌炎患者和种系PD-1中的初步数据。 ICI 心肌炎敲除小鼠模型 (MRL-Pdcd1-/-) 展示了克隆扩增的群体 细胞毒性效应 CD8+ T 细胞被认为在这种疾病中发挥着关键作用，趋化因子上调 RANTES（CCL5）及其受体（CCR5）朱大侠认为ICI心肌炎是由克隆性引起的。 心脏中细胞毒性效应 CD8+ T 细胞的扩增，其发病机制是通过来自 CCL5，她的目标是使用单细胞 RNA-seq/单细胞 TCR 测序和 T 细胞来测试这一假设 过继转移实验（目标 1），以及 MRL-Pdcd1-/- 小鼠中 CCR5 的离体/体内敲除 （目标 2）。 尽管患者心脏组织的 T 细胞克隆分析表明存在心脏特异性抗原 在 ICI 诱发的心肌炎中，此类抗原的身份仍然难以理解。 这种疾病可能会给 T 细胞介导的心肌损伤带来新的见解。 Zhu Kevins博士认为ICI诱发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 细胞激活/克隆扩增的抗原，导致心肌炎症。 她将利用名为 GLIPH（通过 Paratope 对淋巴细胞相互作用进行分组）的新型计算算法 热点）鉴定 ICI 心肌炎的候选致病抗原朱博士的工作将弥合重大问题。 心脏炎症领域的知识差距并确定罪魁祸首 T 细胞亚群和致病因素 该提案的完成将为 ICI 心肌炎和 T 细胞诱导的心肌损伤中的抗原提供研究。 朱博士成功转型为研究免疫的独立医师科学家的平台 心脏炎症/毒性的机制。