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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.
摘要：
淋巴细胞活化基因3（LAG3），在活化的T细胞上表达的免疫检查点分子，作为免疫反应的负调节剂。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，有助于T细胞功能障碍。纤维蛋白原样蛋白1（FGL1）已被确定为LAG3的主要配体，并且FGL1/LAG3相互作用形成了导致肿瘤免疫逃避的新型免疫检查点途径。此外,泛素特异性肽酶7（USP7）在癌症发展中起着至关重要的作用。在这项研究中，我们研究了USP7在调节FGL1介导的肝癌免疫逃避中的作用。我们表明，USP7的敲低或用USP7抑制剂P5091处理通过促进Hepa1-6异种移植小鼠和与T细胞共培养的HepG2或Huh7细胞中的CD8+T细胞活性来抑制肝癌生长，而USP7过表达产生相反的效果。我们发现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，转录激活FGL1，并减弱CD8+T细胞活性，导致肝癌生长。有趣的是,USP7也可以在正反馈回路中被PRDM1转录刺激。P5091，USP7的抑制剂，能够下调FGL1的表达，从而增强CD8+T细胞活性。在具有免疫能力的肝癌小鼠模型中，与单独使用抗LAG3治疗相比,USP7和LAG3的双重阻断导致了更好的抗肿瘤活性.我们得出的结论是，USP7通过USP7/PRDM1正反馈回路对肝癌中FGL1的产生降低CD8T细胞活性;USP7可能是肝癌免疫治疗的有希望的靶标。
