Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, 75390-9093, United States.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390-9093, United States; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390-9093, United States; Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, 75390-9093, United States.
Semin Cancer Biol. 2020 Aug;64:93-101. doi: 10.1016/j.semcancer.2019.06.012. Epub 2019 Jul 19.
Immune checkpoint inhibitors have emerged as a remarkable treatment option for diverse cancer types. However, a significant number of patients on checkpoint inhibitors develop immune-related adverse events (irAEs) affecting a wide variety of organs. These events, which may reflect enhanced T cell activation, are unpredictable, heterogeneous, and in some instances permanent or life-threatening. It is not clear whether these toxicities are distinct from conventional autoimmune diseases or whether the manifestation of irAEs is associated with therapeutic efficacy. Studies across the spectrum of basic, preclinical and clinical research deciphering the role of genetics, epigenetics, gut microbiota and underlying immune status of patients who develop irAEs are required to gain a deeper mechanistic understanding. Insights gained from such studies will facilitate identification of biomarkers for optimal treatment and clinical management of patients. In this Review, we provide basic and clinical understanding of immune checkpoint inhibitors and irAEs. We discuss the connection between immune system, autoimmunity and cancer; immune checkpoint inhibitors and associated autoimmune toxicities; insights into potential underlying mechanisms of irAEs; impact of autoimmune diagnosis on cancer outcome; and management of irAEs.
免疫检查点抑制剂已成为多种癌症类型的一种显著治疗选择。然而，相当数量的接受检查点抑制剂治疗的患者会出现影响多种器官的免疫相关不良反应 (irAE)。这些反映 T 细胞过度激活的事件是不可预测的、异质的，在某些情况下是永久性的或危及生命的。目前尚不清楚这些毒性是否与传统的自身免疫性疾病不同，或者 irAE 的表现是否与治疗效果相关。需要开展从基础研究、临床前研究到临床研究的一系列研究，以深入了解遗传学、表观遗传学、肠道微生物组和发生 irAE 的患者潜在免疫状态的作用。从这些研究中获得的见解将有助于确定生物标志物，以优化 irAE 患者的治疗和临床管理。在这篇综述中，我们提供了对免疫检查点抑制剂和 irAE 的基础和临床理解。我们讨论了免疫系统、自身免疫和癌症之间的联系；免疫检查点抑制剂和相关的自身免疫毒性；irAE 潜在机制的见解；自身免疫诊断对癌症结局的影响；以及 irAE 的管理。
