Cleveland Clinic, Cleveland, OH, United States.
University of Milan, Department of Clinical Sciences and Community Health and Rheumatology Division, ASST Pini-CTO Hospital, Milan, Italy.
J Autoimmun. 2020 Dec;115:102546. doi: 10.1016/j.jaut.2020.102546. Epub 2020 Sep 24.
The T-cell response is regulated by the balance between costimulatory and coinhibitory signals. Immune checkpoints are essential for efficient T-cell activation, but also for maintaining self-tolerance and protecting tissues from damage caused by the immune system, and for providing protective immunity. Modulating immune checkpoints can serve diametric goals, such that blocking a coinhibitory molecule can unleash anti-cancer immunity whereas stimulating the same molecule can reduce an over-reaction in autoimmune disease. The purpose of this review is to examine the regulation of T-cell costimulation and coinhibition, which is central to the processes underpinning autoimmunity, transplant rejection and immune evasion in cancer. We will focus on the immunomodulation agents that regulate these unwanted over- and under-reactions. The use of such agents has led to control of symptoms and slowing of progression in patients with rheumatoid arthritis, reduced rejection rates in transplant patients, and prolonged survival in patients with cancer. The management of immune checkpoint inhibitor treatment in certain challenging patient populations, including patients with pre-existing autoimmune conditions or transplant patients who develop cancer, as well as the management of immune-related adverse events in patients receiving antitumor therapy, is examined. Finally, the future of immune checkpoint inhibitors, including examples of emerging targets that are currently in development, as well as recent insights gained using new molecular techniques, is discussed. T-cell costimulation and coinhibition play vital roles in these diverse therapeutic areas. Targeting immune checkpoints continues to be a powerful avenue for the development of agents suitable for treating autoimmune diseases and cancers and for improving transplant outcomes. Enhanced collaboration between therapy area specialists to share learnings across disciplines will improve our understanding of the opposing effects of treatments for autoimmune disease/transplant rejection versus cancer on immune checkpoints, which has the potential to lead to improved patient outcomes.
T 细胞反应受共刺激和共抑制信号的平衡调节。免疫检查点对于有效的 T 细胞激活至关重要，但也对于维持自身耐受和保护组织免受免疫系统损伤以及提供保护性免疫至关重要。调节免疫检查点可以达到截然相反的目的，例如阻断共抑制分子可以释放抗癌免疫，而刺激相同的分子可以减少自身免疫性疾病中的过度反应。本综述的目的是检查 T 细胞共刺激和共抑制的调节，这是自身免疫、移植排斥和癌症中免疫逃避的核心过程。我们将重点关注调节这些过度和不足反应的免疫调节剂。这些药物的使用导致类风湿关节炎患者症状得到控制，进展速度减慢，移植患者排斥率降低，癌症患者生存率延长。检查了在某些具有挑战性的患者群体中使用免疫检查点抑制剂治疗的情况，包括患有预先存在的自身免疫性疾病的患者或发生癌症的移植患者，以及接受抗肿瘤治疗的患者发生免疫相关不良反应的管理。最后，讨论了免疫检查点抑制剂的未来，包括目前正在开发的新兴靶点的例子，以及使用新分子技术获得的最新见解。T 细胞共刺激和共抑制在这些不同的治疗领域中发挥着重要作用。靶向免疫检查点仍然是开发适合治疗自身免疫性疾病和癌症以及改善移植结果的药物的有力途径。治疗领域专家之间加强合作，在学科之间分享经验，将提高我们对自身免疫性疾病/移植排斥与癌症治疗对免疫检查点的相反作用的理解，这有可能导致患者预后的改善。
