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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

基本信息

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
项目类别：
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

项目摘要

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