Checkpoint receptor blockers, known to act by blocking the pathways that inhibit immune cell activation and stimulate immune responses against tumor cells, have been immensely successful in the treatment of cancer. Among several checkpoint receptors of immune cells, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), T-cell immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin-3 (TIM-3) and lymphocyte activation gene 3 (LAG-3) are the most commonly targeted checkpoints for cancer immunotherapy. Six drugs including one CTLA-4 blocker (ipilimumab), two PD-1 blockers (nivolumab and pembrolizumab) and three PD-L1 blockers (atezolizumab, avelumab and durvalumab) are approved for the treatment of different types of cancers including both solid tumors such as melanoma, lung cancer, head and neck cancer, bladder cancer and Merkel cell cancer as well as hematological tumors such as classic Hodgkin's lymphoma. The main problem with checkpoint blockers is that only a fraction of patients respond to the therapy. Insufficient immune activation is considered as one of the main reason for low response rates and combination of checkpoint blockers has been proposed to increase the response rates. The combination of checkpoint blockers was successful in melanoma but had significant adverse events. A combination that is selected based on the mechanistic differences between checkpoints and the differences in expression of checkpoints and their ligands in the tumor microenvironment could have a synergistic effect in a given cancer subtype and also have a manageable safety profile. This review aims to help in design of optimal checkpoint blocker combinations by discussing the mechanistic details and outlining the subtle differences between major checkpoints targeted for cancer immunotherapy.

中文翻译：

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免疫检查点的机械概述，以支持在癌症免疫治疗中合理设计其组合。

已知通过阻断抑制免疫细胞活化和刺激针对肿瘤细胞的免疫反应的途径起作用的检查点受体阻滞剂，在治疗癌症方面已取得了巨大成功。在免疫细胞的几个检查点受体中，细胞毒性T淋巴细胞相关蛋白4（CTLA-4），程序性细胞死亡蛋白1（PD-1），T细胞免疫球蛋白和ITIM结构域（TIGIT），T细胞免疫球蛋白-3（TIM-3）和淋巴细胞激活基因3（LAG-3）是癌症免疫疗法最常用的检查点。包括一种CTLA-4阻滞剂（ipilimumab），两种PD-1阻滞剂（nivolumab和pembrolizumab）和三种PD-L1阻滞剂（atezolizumab，avelumab和durvalumab）在内的六种药物已被批准用于治疗不同类型的癌症，包括两种实体瘤。如黑色素瘤，肺癌，头颈癌，膀胱癌和默克尔细胞癌，以及血液肿瘤，例如经典霍奇金淋巴瘤。检查点阻滞剂的主要问题是只有一小部分患者对该疗法有反应。免疫激活不足被认为是应答率低的主要原因之一，并且已提出结合使用检查点阻断剂来提高应答率。检查点阻滞剂的组合在黑色素瘤中成功，但有重大不良事件。基于检查点之间的机械差异以及肿瘤微环境中检查点及其配体的表达差异选择的组合可以在给定的癌症亚型中产生协同效应，并且还具有可控的安全性。