Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
Curr Med Chem. 2020;27(15):2402-2448. doi: 10.2174/0929867325666181106114421.
The immune system actively counteracts the tumorigenesis process; a breakout of the immune system function, or its ability to recognize transformed cells, can favor cancer development. Cancer becomes able to escape from immune system control by using multiple mechanisms, which are only in part known at a cellular and molecular level. Among these mechanisms, in the last decade, the role played by the so-called "inhibitory immune checkpoints" is emerging as pivotal in preventing the tumor attack by the immune system. Physiologically, the inhibitory immune checkpoints work to maintain the self-tolerance and attenuate the tissue injury caused by pathogenic infections. Cancer cell exploits such immune-inhibitory molecules to contrast the immune intervention and induce tumor tolerance. Molecular agents that target these checkpoints represent the new frontier for cancer treatment. Despite the heterogeneity and multiplicity of molecular alterations among the tumors, the immune checkpoint targeted therapy has been shown to be helpful in selected and even histologically different types of cancer, and are currently being adopted against an increasing variety of tumors. The most frequently used is the moAb-based immunotherapy that targets the Programmed Cell Death 1 protein (PD-1), the PD-1 Ligand (PD-L1) or the cytotoxic T lymphocyte antigen-4 (CTLA4). However, new therapeutic approaches are currently in development, along with the discovery of new immune checkpoints exploited by the cancer cell. This article aims to review the inhibitory checkpoints, which are known up to now, along with the mechanisms of cancer immunoediting. An outline of the immune checkpoint targeting approaches, also including combined immunotherapies and the existing trials, is also provided. Notwithstanding the great efforts devoted by researchers in the field of biomarkers of response, to date, no validated FDA-approved immunological biomarkers exist for cancer patients. We highlight relevant studies on predictive biomarkers and attempt to discuss the challenges in this field, due to the complex and largely unknown dynamic mechanisms that drive the tumor immune tolerance.
免疫系统积极对抗肿瘤发生过程；免疫系统功能的爆发，或其识别转化细胞的能力，可能有利于癌症的发展。癌症通过多种机制逃脱免疫系统的控制，这些机制在细胞和分子水平上只有部分被了解。在这些机制中，在过去十年中，所谓的“抑制性免疫检查点”所起的作用在阻止免疫系统对肿瘤的攻击方面变得至关重要。从生理上讲，抑制性免疫检查点的作用是维持自身耐受和减轻由致病感染引起的组织损伤。癌细胞利用这些免疫抑制分子来对抗免疫干预并诱导肿瘤耐受。针对这些检查点的分子药物代表了癌症治疗的新前沿。尽管肿瘤之间存在分子改变的异质性和多样性，但针对免疫检查点的靶向治疗已被证明对某些甚至组织学上不同类型的癌症有效，并且目前正在针对越来越多种类的肿瘤采用。最常用的是基于 moAb 的免疫疗法，其针对程序性细胞死亡 1 蛋白（PD-1）、PD-1 配体（PD-L1）或细胞毒性 T 淋巴细胞抗原-4（CTLA4）。然而，目前正在开发新的治疗方法，同时发现癌细胞利用的新免疫检查点。本文旨在回顾迄今为止已知的抑制性检查点，以及癌症免疫编辑的机制。还概述了免疫检查点靶向方法，包括联合免疫疗法和现有的试验。尽管研究人员在生物标志物反应方面做出了巨大努力，但迄今为止，癌症患者没有经过验证的 FDA 批准的免疫生物标志物。我们强调了关于预测生物标志物的相关研究，并尝试讨论了该领域的挑战，这是由于驱动肿瘤免疫耐受的复杂且很大程度上未知的动态机制所致。
