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

项目摘要 免疫检查点是免疫系统的正常部分，可防止T细胞发生自身反应。癌 细胞通过过表达这些免疫检查点来开发逃避细胞毒性T细胞清除的方法。 免疫检查点抑制剂（ICI）是增强抗肿瘤反应和恢复肿瘤的抗体， 监视和清除一种这样的药物作用于一种称为细胞毒性T淋巴细胞的检查点蛋白质， 其他免疫检查点抑制剂靶向程序性死亡-1（PD-1）， 其配体（PD-L1）。癌症免疫疗法已经导致某些癌症患者的预期寿命显著增加。 实体瘤然而，ICI具有严重的免疫相关不良反应，包括肝毒性和肝损伤， 特别是当使用CTLA 4和PD-L1抑制剂的组合时。当免疫介导的肝损伤 检查点抑制剂（ILICI）是严重的，必须停止免疫治疗。此应用程序的总体目标 是调查ILICI的机制，并最终设计有针对性的解决方案，以减轻这种形式的 肝毒性ICIs如何靶向肝细胞，哪些细胞是细胞死亡的效应子，哪些细胞死亡 目前还没有研究一种细胞死亡模式是否占主导地位。在这一提议中， 我们描述了ILICI的小鼠模型，我们建议研究导致肝脏ILICI的潜在细胞死亡途径。 损伤通过了解肝损伤如何发生以及肝细胞如何死亡，我们计划设计靶向治疗， 肝脏，以预防和治疗肝毒性，使救生免疫治疗的延续。

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.