Tumor immune checkpoints and their associated inhibitors

Abstract

Immunological evasion is one of the defining characteristics of cancers, as the immune modification of an immune checkpoint (IC) confers immune evasion capabilities to tumor cells. Multiple ICs, such as programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), can bind to their respective receptors and reduce tumor immunity in a variety of ways, including blocking immune cell activation signals. IC blockade (ICB) therapies targeting these checkpoint molecules have demonstrated significant clinical benefits. This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers. Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment. In this review, we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels, including epigenetic regulation, transcriptional regulation, and post-translational modifications. In addition, we provide a summary of the medications targeting various nodes in the regulatory pathway, and highlight the potential of newly identified IC molecules, focusing on their potential implications for cancer diagnostics and immunotherapy.

概要

包括程序性细胞死亡蛋白1(PD-1)和细胞毒性T淋巴细胞相关抗原4(CTLA-4)在内的免疫检查点蛋白,可以与各自的受体结合,以阻断免疫细胞的激活信号等方式促进肿瘤细胞免疫逃逸。这种由免疫检查点的免疫修饰赋予的肿瘤细胞免疫规避能力,使得免疫逃逸成为肿瘤的重要特征之一。靶向上述分子的免疫检查点阻断(ICB)疗法通过抗体与特定小分子抑制剂抑制肿瘤关键信号通路,破解肿瘤患者的免疫耐受,已表现出优异的临床效益。因此,破译这些免疫检查点分子的作用和调节机制将为临床治疗提供关键的理论指导。在这篇综述中,我们总结了目前关于这些免疫检查点分子在多个层面上的功能和调节机制,包括表观遗传调节、转录调节和翻译后修饰。此外,我们还对针对调控途径中各个节点的药物进行了总结,进一步阐明新鉴定的免疫检查点分子的临床潜力,重点介绍了它们对癌症诊断和免疫治疗的潜在意义。