Division of Immunology-Oncology, Research Center Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada; Département de Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
Division of Immunology-Oncology, Research Center Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada; Département de Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
Semin Immunol. 2019 Apr;42:101295. doi: 10.1016/j.smim.2019.101295.
The past few years have witnessed exciting progress in the application of immune check-point blockade (ICB) for the treatment of various human cancers. ICB was first used against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to demonstrate durable anti-tumor responses followed by ICB against programmed cell death-1 (PD-1) or its ligand, PD-L1. Present approaches involve the use of combinations of blocking antibodies against CTLA-4, PD-1 and other inhibitory receptors (IRs) such as TIM3, TIGIT and LAG3. Despite this success, most patients are not cured by ICB therapy and there are limitations to the use of antibodies including cost, tumor penetration, the accessibility of receptors, and clearance from the cell surface as well as inflammatory and autoimmune complications. Recently, we demonstrated that the down-regulation or inhibition of glycogen synthase kinase 3 (GSK-3) down-regulates PD-1 expression in infectious diseases and cancer (Taylor et al., 2016 Immunity 44, 274-86; 2018 Cancer Research 78, 706-717; Krueger and Rudd 2018 Immunity 46, 529-531). In this Review, we outline the use of small molecule inhibitors (SMIs) that target intracellular pathways for co-receptor blockade in cancer immunotherapy.
在过去的几年中，免疫检查点阻断（ICB）在治疗各种人类癌症方面的应用取得了令人兴奋的进展。首先使用细胞毒性 T 淋巴细胞相关蛋白 4（CTLA-4）的抑制剂来证明持久的抗肿瘤反应，随后使用程序性细胞死亡蛋白 1（PD-1）或其配体 PD-L1 的抑制剂。目前的方法包括使用针对 CTLA-4、PD-1 和其他抑制性受体（IRs）如 TIM3、TIGIT 和 LAG3 的阻断抗体的组合。尽管取得了这些成功，但大多数患者并未通过 ICB 治疗治愈，并且抗体的使用存在局限性，包括成本、肿瘤穿透性、受体的可及性以及从细胞表面清除以及炎症和自身免疫并发症。最近，我们证明糖原合酶激酶 3（GSK-3）的下调或抑制可下调传染病和癌症中的 PD-1 表达（Taylor 等人，2016 年《免疫》44,274-86；2018 年《癌症研究》78,706-717；Krueger 和 Rudd 2018 年《免疫》46,529-531）。在这篇综述中，我们概述了使用小分子抑制剂（SMIs）靶向癌症免疫疗法中的共受体阻断细胞内途径的用途。
