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中防止T细胞自身反应的正常部分。癌 细胞通过过度表达这些免疫检查点来逃避细胞毒性T细胞的清除。 免疫检查点抑制物(ICI)是增强抗肿瘤反应和恢复肿瘤的抗体 监视和许可。其中一种药物对一种名为细胞毒性T淋巴细胞的检查点蛋白起作用-- 相关蛋白4(CTLA-4)，而其他免疫检查点抑制剂靶向程序性死亡-1(PD-1)和 其配体(Pd-L1)。癌症免疫疗法从某些方面显著延长了预期寿命 实体瘤。然而，ICIS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CTLA4和PD-L1抑制剂的组合时。当免疫介导的肝损伤来自 检查点抑制药(ILICI)很严重，必须停止免疫治疗。此应用程序的总体目标是 是研究ILICI的机制，并最终设计有针对性的解决方案来缓解这种形式的 肝脏毒性。肝细胞如何被ICIS定位，哪些细胞是细胞死亡的效应者，哪些细胞死亡 参与的途径很多，但是否有一种细胞死亡模式是主导的还没有研究。在这份提案中， 我们描述了一种ILICI的小鼠模型，并建议研究导致肝脏的潜在细胞死亡途径 受伤。通过低估肝损伤是如何发生的，以及肝细胞是如何死亡的，我们计划设计有针对性的治疗方法 预防和治疗肝脏毒性，使挽救生命的免疫疗法得以继续。

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.