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.

项目总结/文摘