Inhibition of USP7 enhances CD8^(+)T cell activity in liver cancer by suppressing PRDM1-mediated FGL1 upregulation  

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

机构地区：[1]Department of Hepatobiliary Oncology,Liver Cancer Center,Tianjin Medical University Cancer Institute and Hospital,National Clinical Research Center for Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin’s Clinical Research Center for Cancer,Tianjin Medical University,Tianjin,300060,China [2]National Key Laboratory of Drug ability Evaluation and Systematic Translational Medicine,Tianjin’s Clinical Research Center for Cancer,Tianjin Key Laboratory of Digestive Cancer/Department of Gastrointestinal Cancer Biology,Tianjin Cancer Institute,Liver Cancer Center,Tianjin Medical University Cancer Institute and Hospital,National Clinical Research Center for Cancer,Tianjin,300060,China

出　　处：《Acta Pharmacologica Sinica》2024年第8期1686-1700,共15页中国药理学报（英文版）

基　　金：supported by the Natural Science Foundation of Tianjin Science and Technology Committee(19YFZCSY00020);the National Natural Science Foundation of China(82372818 to XDZ,82103066 to GY;82302887 to HFY,82303210 to YFW);the China Postdoctoral Science Foundation(2022M712389 to HFY;2023M742621 to LNZ,2023M732624 to YFW);Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-009A to WL);“14th Five-Year Plan”Tumor Prevention and Treatment Research Project of Tianjin Medical University Cancer Institute and Hospital(No.YZ-03).

摘　　要：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.

关 键 词：USP7 PRDM1 FGL1 CD8^(+)T cell activity immune evasion liver cancer 

分 类 号：R730.1[医药卫生—肿瘤]