Identification of Causal Antigens in Immune Checkpoint Inhibitor-Induced Myocarditis

免疫检查点抑制剂诱发的心肌炎的致病抗原的鉴定

• 批准号: 10022140
• 负责人: Han Zhu
• 金额: $ 1.77万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-14 至 2020-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022140
• 关键词: Acute; Adjuvant Therapy; Advanced Malignant Neoplasm; Adverse drug effect; Affect; Age; Algorithms; Animals; Antibodies; Antibody Binding Sites; Antigen-Antibody Complex; Antigens; Arrhythmia; Atherosclerosis; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autopsy; Biological; Biopsy; Blood; CD8-Positive T-Lymphocytes; Cancer Patient; Cardiac; Cardiac Death; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Clinical; Clonal Expansion; Clone Cells; Computational algorithm; Cytometry; Cytotoxic T-Lymphocytes; DNA sequencing; Databases; Development; Disease; Ensure; Epitopes; Flow Cytometry; Goals; Grouping; Heart; Heart failure; Histopathology; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunohistochemistry; Immunologics; Immunophenotyping; Infiltration; Inflammation; Inflammatory; Knock-out; Knowledge; Lead; Life; Light; Lymphocyte; Lymphocytic Infiltrate; Malignant Neoplasms; Mediating; Mentors; Metastatic Melanoma; Methods; Monoclonal Antibodies; Mus; Myocardial; Myocarditis; Myocardium; Non-Small-Cell Lung Carcinoma; Pathologic; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Physicians; Play; Population; Prevention; Process; Reaction; Regulatory Pathway; Reporting; Role; Safety; Sampling; Scientist; Site; Specificity; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Therapeutic; Tissues; Training; Variant; age group; cell type; checkpoint therapy; cohort; cross reactivity; cytokine; cytotoxicity; heart damage; insight; lupus-like; mouse model; myocardial damage; neoplastic cell; new therapeutic target; novel; programmed cell death ligand 1; programmed cell death protein 1; response; side effect; sudden cardiac death; time use

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.

项目摘要/摘要 心肌炎，心脏的病理炎症，是心脏猝死的严重原因，影响了所有年龄的患者 组。免疫检查点抑制剂（ICI）是对细胞毒性T细胞T细胞抗原-4（CTLA-4）的单克隆抗体或 程序性死亡1（PD-1）/程序性死亡-1配体（PD-1L）用作新型癌症治疗剂，以释放内在 针对肿瘤细胞的T细胞细胞毒性制动。尽管现在依靠ICI来治疗许多高级癌症，但 据报道，暴发性心肌炎是这些药物的生命副作用，导致严重的心律不齐，心脏 失败和死亡。在组织病理学下，在心脏中发现了急性淋巴细胞浸润，并有多种证据 指向T细胞和抗原介导的现象。尽管对患者心脏组织的T细胞克隆分析表明 在ICI诱导的心肌炎中存在心脏特异性抗原，这种抗原的身份仍然难以捉摸。 了解该疾病中的罪魁祸首可能会导致对T细胞介导的机制的新见解 心肌损伤。我假设ICI诱发的心肌炎是由心脏特异性自身 - 触发T细胞激活和克隆膨胀的抗原，导致心肌炎症。目标的目标 研究是使用一种称为cytof的先进的免疫表型技术来表征T细胞子集，然后 使用单细胞T细胞受体测序和一种称为GLIPH的新型计算算法（分组 副热点与淋巴细胞相互作用），以识别负责ICI-的T细胞激活的特定表位 诱导小鼠和人类的心肌损伤。通过完成该项目，我将发现关键的见解 ICI诱导心肌炎的生物学机制将弥合有关T细胞在T中的作用的主要知识差距 介导心肌损伤。我的结果将回答哪种免疫细胞类型在 ICI诱导的心肌炎，并鉴定引起疾病的抗原引起心脏毒性。有越来越多的证据 提示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，性动脉粥样硬化。我作为医师科学家的长期目标是阐明 心脏中病理炎症的机制有助于治愈心血管疾病并成为该领域的领导者 心脏炎症。