Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, Maryland, 20993, USA.
Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington, 98195, USA.
AAPS J. 2021 Aug 16;23(5):99. doi: 10.1208/s12248-021-00629-2.
Immune checkpoint inhibitors (ICIs) represent a promising therapy for many types of cancer. However, only a portion of patients respond to this therapy and some patients develop clinically significant immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI), an immune-related adverse event (irAE) that may require the interruption or termination of treatment and administration of systemic corticosteroids or other immunosuppressive agents. Although the incidence of ILICI is lower with monotherapy, the surge in combining ICIs with chemotherapy, targeted therapy, and combination of different ICIs has led to an increase in the incidence and severity of ILICI - a major challenge for development of effective and safe ICI therapy. In this review, we highlight the importance and contribution of the liver microenvironment to ILICI by focusing on the emerging roles of resident liver cells in modulating immune homeostasis and hepatocyte regeneration, two important decisive factors that dictate the initiation, progression, and recovery from ILICI. Based on the proposed contribution of the liver microenvironment on ICILI, we discuss the clinical characteristics of ILICI in patients with preexisting liver diseases, as well as the challenges of identifying prognostic biomarkers to guide the clinical management of severe ILICI. A better understanding of the liver microenvironment may lead to novel strategies and identification of novel biomarkers for effective management of ILICI.
免疫检查点抑制剂 (ICIs) 代表了许多类型癌症的一种有前途的治疗方法。然而，只有一部分患者对这种治疗有反应，一些患者会出现由免疫检查点抑制剂引起的临床显著免疫介导的肝损伤 (ICILI)，这是一种免疫相关的不良反应 (irAE)，可能需要中断或终止治疗，并给予全身皮质类固醇或其他免疫抑制剂。虽然单药治疗的 ICILI 发生率较低，但随着免疫检查点抑制剂与化疗、靶向治疗以及不同免疫检查点抑制剂联合的应用增加，ICILI 的发生率和严重程度也有所增加，这是开发有效和安全的免疫检查点抑制剂治疗的主要挑战。在这篇综述中，我们通过关注驻留肝细胞在调节免疫稳态和肝细胞再生方面的新作用，强调了肝微环境对 ICILI 的重要性和贡献，这两个重要决定因素决定了 ILICI 的启动、进展和恢复。基于对 ICILI 中肝微环境的拟议贡献，我们讨论了患有现有肝脏疾病的患者中 ILICI 的临床特征，以及识别预后生物标志物以指导严重 ILICI 临床管理的挑战。对肝微环境的更好理解可能会导致为有效管理 ILICI 提供新的策略和识别新的生物标志物。
