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

Acta Pharmacologica Sinica (2024)Cite this article

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.

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Fig. 1: Inhibition of USP7 limits tumor growth via promoting CD8+ T cell activity in vivo and in vitro.
Fig. 2: USP7 attenuates CD8+ T cell activity by upregulating FGL1 in liver cancer.
Fig. 3: Activated transcription of FGL1 by PRDM1 attenuates anti-tumor immunity.
Fig. 4: USP7 interacts with PRDM1 to promote its deubiquitination and stabilization.
Fig. 5: PRDM1 transcriptionally activates USP7 in liver cancer.
Fig. 6: USP7-elevated PRDM1 inhibits CD8+ T cell activation via modulating FGL1.
Fig. 7: USP7 inhibition enhances the sensitivity of LAG3 mAb in immunotherapy of liver cancer.
Fig. 8: Inhibition of USP7 triggers the CD8+ T cell activity by modulating transcriptional factor PRDM1 to block FGL1 in liver cancer.

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Acknowledgements

This work was 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), and “14th Five-Year Plan” Tumor Prevention and Treatment Research Project of Tianjin Medical University Cancer Institute and Hospital (No. YZ-03).

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  1. These authors contributed equally: Lin-lin Sun, Li-na Zhao, Jiao Sun

Authors and Affiliations

  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

    Lin-lin Sun, Jiao Sun, Ning-ning Zhang & Wei Lu

  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

    Li-na Zhao, Hong-feng Yuan, Yu-fei Wang, Chun-yu Hou, Pan Lv, Hui-hui Zhang, Guang Yang & Xiao-dong Zhang

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Contributions

LLS performed most of the experiments; LNZ, JS, HHZ, and PL accomplished some of the in vitro and in vivo experiments; YFW, HFY, and CYH accomplished some RNA-seq analysis; WL, XDZ, NNZ, and GY conceived and designed the project; LLS and XDZ wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Guang Yang, Ning-ning Zhang, Xiao-dong Zhang or Wei Lu.

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Sun, Ll., Zhao, Ln., Sun, J. et al. Inhibition of USP7 enhances CD8+ T cell activity in liver cancer by suppressing PRDM1-mediated FGL1 upregulation. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01263-2

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