天津医科大学Wei Lu，Ning-ning Zhang，国家肿瘤临床研究中心Xiao-dong Zhang和Guang Yang共同合作，近期取得重要工作进展。他们研究提出，抑制USP7可通过抑制PRDM1介导的FGL1上调来增强肝癌中CD8⁺ T细胞的活性。相关研究成果2024年4月8日在线发表于《中国药理学报》杂志上。

据介绍，淋巴细胞活化基因3（LAG3）是一种在活化T细胞上表达的免疫检查点分子，是免疫反应的负调节因子。肿瘤微环境中持续的抗原暴露导致T细胞上持续的LAG3表达，从而导致T细胞功能障碍。纤维蛋白原样蛋白1（FGL1）已被鉴定为LAG3的主要配体，FGL1/LAG3相互作用形成了一种新的免疫检查点途径，导致肿瘤免疫逃避。此外，泛素特异性肽酶7（USP7）在癌症的发展中起着至关重要的作用。

研究人员探讨了USP7在调节FGL1介导的癌症免疫逃避中的作用。研究人员发现，在Hepa1-6异种移植物小鼠和与T细胞共同培养的HepG2或Huh7细胞中，USP7的敲低或用USP7抑制剂P5091治疗通过促进CD8⁺  T细胞活性来抑制癌症生长，而USP7过表达产生相反的效果。

研究人员发现，USP7通过转录因子PR结构域锌指蛋白1（PRDM1）的去泛素化上调HepG2和Huh7细胞中的FGL1，从而转录激活FGL1，并减弱CD8⁺ T细胞活性，导致肝癌生长。USP7也可以在正反馈回路中被PRDM1转录刺激。P5091是USP7的抑制剂，能够下调FGL1的表达，从而增强CD8⁺ T细胞的活性。在具有免疫活性的肝癌小鼠模型中，与单独的抗LAG3治疗相比，USP7和LAG3的双重阻断导致了优越的抗肿瘤活性。

总之，在癌症中，USP7通过USP7/PRDM1对肝癌中FGL1产生的正反馈回路来降低CD8⁺ T细胞活性；USP7可能是肝癌免疫治疗的一个有前景的靶点。

附：英文原文

Title: Inhibition of USP7 enhances CD8+ T cell activity in liver cancer by suppressing PRDM1-mediated FGL1 upregulation

Author: Sun, Lin-lin, Zhao, Li-na, Sun, Jiao, Yuan, Hong-feng, Wang, Yu-fei, Hou, Chun-yu, Lv, Pan, Zhang, Hui-hui, Yang, Guang, Zhang, Ning-ning, Zhang, Xiao-dong, Lu, Wei

Issue&Volume: 2024-04-08

Abstract: Lymphocyte activation gene 3 (LAG3), an immune checkpoint molecule expressed on activated T cells, functions as a negative regulator of immune responses. Persistent antigen exposure in the tumor microenvironment results in sustained LAG3 expression on T cells, contributing to T cell dysfunction. Fibrinogen-like protein 1 (FGL1) has been identified as a major ligand of LAG3, and FGL1/LAG3 interaction forms a novel immune checkpoint pathway that results in tumor immune evasion. In addition, ubiquitin-specific peptidase 7 (USP7) plays a crucial role in cancer development. In this study we investigated the role of USP7 in modulation of FGL1-mediated liver cancer immune evasion. We showed that knockdown of USP7 or treatment with USP7 inhibitor P5091 suppressed liver cancer growth by promoting CD8+ T cell activity in Hepa1-6 xenograft mice and in HepG2 or Huh7 cells co-cultured with T cells, whereas USP7 overexpression produced the opposite effect. We found that USP7 upregulated FGL1 in HepG2 and Huh7 cells by deubiquitination of transcriptional factor PR domain zinc finger protein 1 (PRDM1), which transcriptionally activated FGL1, and attenuated the CD8+ T cell activity, leading to the liver cancer growth. Interestingly, USP7 could be transcriptionally stimulated by PRDM1 as well in a positive feedback loop. P5091, an inhibitor of USP7, was able to downregulate FGL1 expression, thus enhancing CD8+ T cell activity. In an immunocompetent liver cancer mouse model, the dual blockade of USP7 and LAG3 resulted in a superior antitumor activity compared with anti-LAG3 therapy alone. We conclude that USP7 diminishes CD8+ T cell activity by a USP7/PRDM1 positive feedback loop on FGL1 production in liver cancer; USP7 might be a promising target for liver cancer immunotherapy.

DOI: 10.1038/s41401-024-01263-2

Source: https://www.nature.com/articles/s41401-024-01263-2