Targeting Cell Death Pathways in Immune-mediated Liver Injury from Checkpoint Inhibitors

检查点抑制剂在免疫介导的肝损伤中靶向细胞死亡途径

• 批准号: 10598102
• 负责人: Lily Dara
• 金额: $ 12.38万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598102
• 关键词: Acetaminophen; Advanced Malignant Neoplasm; Adverse effects; Adverse event; Antitumor Response; Apoptosis; Birth; CASP3 gene; CTLA4 gene; Cell Death; Cell Separation; Cessation of life; Cytometry; Cytotoxic T-Lymphocytes; Data; Development; Diarrhea; Dose; Drug Side Effects; Effector Cell; Enterocolitis; Event; Fractionation; Goals; HTATIP2 gene; Hepatocyte; Hepatotoxicity; High Prevalence; Human; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune system; Immunity; Immunological Models; Immunotherapy; Inflammasome; Inflammation; Intestinal permeability; Intestines; Lead; Leaky Gut; Life; Life Expectancy; Ligands; Liver; Mediating; Mediator; Modeling; Mus; Natural Immunity; Necrosis; Pathway interactions; Patients; Phenotype; Population; Proteins; RIPK1 gene; Reporting; Role; Signal Transduction; Solid Neoplasm; Time; Toxic effect; antibody inhibitor; autoreactive T cell; autoreactivity; cancer cell; cancer immunotherapy; cancer therapy; cost; design; drug action; experimental study; gut inflammation; gut-liver axis; human model; immune cell infiltrate; immune checkpoint; immune-related adverse events; inhibitor; knock-down; liver inflammation; liver injury; monocyte; mouse model; neoplastic cell; overexpression; prevent; programmed cell death ligand 1; programmed cell death protein 1; recruit; targeted treatment; tumor

Project Summary Immune checkpoints are a normal part of the immune system that prevent T cells from autoreactivity. Cancer cells develop ways of evading clearance from cytotoxic T Cells by overexpressing these immune checkpoints. Immune Checkpoint Inhibitors (ICI) are antibodies that augment anti-tumor responses and restore tumor surveillance and clearance. One such drug acts against a checkpoint protein called cytotoxic T-lymphocyte- associated protein 4 (CTLA-4), while other immune checkpoint inhibitors target programmed death-1 (PD-1) and its ligand (PD-L1). Cancer immunotherapy has resulted in dramatically increased life expectancy from certain solid tumors. However, ICIs have serious immune related adverse effects including hepatotoxicity and liver injury, especially when combination CTLA4 and PD-L1 inhibitors are used. When Immune-mediated Liver Injury from Checkpoint Inhibitors (ILICI) is severe, immunotherapy must be discontinued. The Overall goal of this application is to investigate the mechanism of ILICI and ultimately design targeted solutions for mitigating this form of hepatotoxicity. How liver cells are targeted by the ICIs, which cells are the effectors of cell death, which cell death pathways are participating, and whether one cell death mode is dominant has not been studied. In this proposal, we describe a mouse model of ILICI and we propose to study the underlying cell death pathway leading to liver injury. By understating how liver injury occurs and how liver cells die, we plan to design targeted therapies to the liver to prevent and treat hepatotoxicity, enabling the continuation of lifesaving immunotherapy.

项目摘要 免疫检查点是防止T细胞自动反应性的免疫系统的正常部分。癌症 细胞通过过度表达这些免疫检查点来发展从细胞毒性T细胞中探索清除的方法。 免疫检查点抑制剂（ICI）是增强抗肿瘤反应并恢复肿瘤的抗体 监视和清除。一种这样的药物对检查点蛋白的作用称为细胞毒性T淋巴细胞 - 相关蛋白质4（CTLA-4），而其他免疫检查点抑制剂靶向编程死亡-1（PD-1）和 它的配体（PD-L1）。癌症免疫疗法已导致某些人的预期寿命大大提高 实体瘤。但是，ICI具有严重的免疫相关的不良反应，包括肝毒性和肝损伤， 特别是当使用CTLA4和PD-L1抑制剂组合时。免疫介导的肝损伤 检查点抑制剂（ILICI）很严重，必须停止免疫疗法。此应用程序的总体目标 是为了研究Ilici的机制，并最终设计了针对性的解决方案，以减轻这种形式 肝毒性。肝细胞如何由ICI靶向，ICI是细胞死亡的效应因子，细胞死亡 途径正在参与，并且尚未研究一种细胞死亡模式。在此提案中， 我们描述了Ilici的小鼠模型，我们建议研究导致肝脏的潜在细胞死亡途径 受伤。通过低估肝损伤的发生以及肝细胞如何死亡，我们计划将目标疗法设计为 肝脏预防和治疗肝毒性，从而能够继续救生免疫疗法。