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 ORCID:

Ai-fu Lin

https://orcid.org/0000-0002-3968-3617

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Journal of Zhejiang University SCIENCE B

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Tumor immune checkpoints and their associated inhibitors


Author(s):  Zerui GAO, Xingyi LING, Chengyu SHI, Ying WANG, Aifu LIN

Affiliation(s):  MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China; more

Corresponding email(s):  linaifu@zju.edu.cn

Key Words:  Immune checkpoint; Immune checkpoint inhibitor; Programmed cell death-ligand 1 (PD-L1); Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4); Lymphocyte activation gene-3 (LAG-3); T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT); B7 family


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Zerui GAO, Xingyi LING, Chengyu SHI, Ying WANG, Aifu LIN. Tumor immune checkpoints and their associated inhibitors[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2200195

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%A Chengyu SHI
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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.

肿瘤免疫检查点及与其相关抑制剂

高泽瑞1,2,3,4,凌幸怡1,2,3,石成瑜1,2,3,王颖1,2,3,林爱福1,2,3,5,6,7
1浙江大学生命科学学院生命系统稳态与保护教育部重点实验室,中国杭州市,310058
2浙江大学癌症研究中心,中国杭州市,310058
3浙江省细胞与基因工程重点实验室,中国杭州市,310058
4浙江大学竺可桢荣誉学院,中国杭州市,310058
5浙江大学医学院附属第一医院乳腺疾病诊治中心,中国杭州市,310058
6浙江大学医学院第四附属医院国际医学院,中国义乌市,322000
7浙江大学-齐鲁制药联合研究院,中国杭州市,310058
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。

关键词组:免疫检查点;免疫检查点抑制剂;PD-L1;CTLA-4;LAG-3;TIGIT;B7家族

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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