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  • E-twenty-six-specific sequence variant 5 (ETV5) facilitates hepatocellular carcinoma progression and metastasis through enhancing polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC)-mediated immunosuppression

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Hepatology
Original research
E-twenty-six-specific sequence variant 5 (ETV5) facilitates hepatocellular carcinoma progression and metastasis through enhancing polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC)-mediated immunosuppression
  1. Zerui Zhang1,
  2. Wenjie Huang2,
  3. Dian Hu1,
  4. Junqing Jiang1,
  5. Jiaqian Zhang1,
  6. Zhangfan Wu1,
  7. Junjie Wen1,
  8. Xiangyuan Luo1,
  9. Yijun Wang1,
  10. Mengyu Sun1,
  11. Siwen Li1,
  12. Yufei Wang1,
  13. Danfei Liu1,
  14. Xiaoping Chen2,
  15. Bixiang Zhang2,
  16. Huifang Liang2,
  17. Yiwei Li3,
  18. Bifeng Liu3,
  19. Shuai Wang4,
  20. Xiao Xu5,6,
  21. Yongzhan Nie7,
  22. Kaichun Wu7,
  23. Daiming Fan7,
  24. Limin Xia1,7,8
  1. 1Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Huazhong University of Science and Technology Tongji Medical College Tongji Hospital, Wuhan, Hubei, China
  2. 2Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Huazhong University of Science and Technology Tongji Medical College Tongji Hospital, Wuhan, Hubei, China
  3. 3The Key Laboratory for Biomedical Photonics of MOE at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics and Molecular Imaging Key Laboratory, Systems Biology Theme, Department of Biomedical Engineering, Huazhong University of Science and Technology College of Life Science and Technology, Wuhan, Hubei, China
  4. 4Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
  5. 5School of Clinical Medicine, Hangzhou Medical College, Hangzhou, China
  6. 6Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
  7. 7State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
  8. 8State KeyLaboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, China
  1. Correspondence to Dr Limin Xia; xialimin{at}tjh.tjmu.edu.cn

Abstract

Background Despite the success of immune checkpoint blockade, a lack of understanding of the hepatocellular carcinoma (HCC) immune microenvironment impedes its development.

Objective We aim to elucidate the essential function of E-twenty-six-specific sequence variant 5 (ETV5) in regulating the immune microenvironment in HCC.

Design Humanised mouse models, murine orthotopic models and diethylnitrosamine/carbon tetrachloride (DEN/CCl4)-induced HCC models were used to examine the function of ETV5. The downstream targets of ETV5 were screened using chromatin immunoprecipitation sequencing, CUT&Tag and RNA sequencing. Immune cells were examined using flow cytometry and immunofluorescence. S100 calcium-binding protein A9 (S100A9) was targeted by neutralising antibodies.

Results Overexpression of ETV5 in HCC cells facilitated HCC metastasis and immune escape by recruiting and enhancing the immunosuppressive capabilities of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, ETV5 transactivated programmed death ligand 1 (PD-L1) and S100A9 expression. Inhibition of S100A9 or myeloid-specific knockout of toll-like receptor 4 (TLR4)/receptor for advanced glycation endproducts (RAGE), the receptors of S100A9, impeded ETV5-induced PMN-MDSC recruitment. Meanwhile, S100A9 within the tumour microenvironment elevated ETV5 expression via the extracellular signal-regulated kinase (ERK)/nuclear factor-kappa B pathway. Additionally, ETV5 transcriptionally upregulated PD-L1 in MDSCs as well, thereby augmenting their immunosuppressive functions. Myeloid-specific Etv5 knockout attenuated HCC progression. We developed monoclonal neutralising-S100A9 antibodies that effectively inhibited ETV5-mediated PMN-MDSC infiltration. Synergistic application of anti-S100A9 or TLR4/RAGE inhibitors with anti-PD-L1 therapy significantly suppressed ETV5-mediated HCC progression.

Conclusion ETV5 facilitates HCC progression and metastasis by promoting the recruitment, infiltration and activation of PMN-MDSCs. Synergistic application of anti-S100A9 or TLR4/RAGE inhibitors with anti-PD-L1 therapy holds great promise as an effective combinational treatment strategy for ETV5-positive HCC.

  • HEPATOCELLULAR CARCINOMA
  • IMMUNOTHERAPY
  • CANCER IMMUNOBIOLOGY

Data availability statement

Data are available upon reasonable request. Data, analytical methods and study materials will be available from the corresponding author upon request.

https://doi.org/10.1136/gutjnl-2024-333944

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    Data availability statement

    Data are available upon reasonable request. Data, analytical methods and study materials will be available from the corresponding author upon request.

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    Footnotes

    • Contributors ZZ performed the experiments, analysed the data and drafted the manuscript. DH, JJ, JZ and ZW assisted in animal experiments. XL, YW, MS, SL, YW, J, and DL assisted in collecting tissue samples. XC, BZ, HL, YL, BL, SW, XX, YN, KW and DF assisted in manuscript editing. LX, WH,and ZZ designed the studies and revised the paper. LX is the guarantor.

    • Funding Research was supported by grants from the National Natural Science Foundation of China No. U23A20451 (LX), No. 82273310 (LX), No. 82173313 (WH), No. 82372917 (WH), the Natural Science Foundation of Hubei Province 2022CFA016 (LX), and the Basic Research Support Program of Huazhong University of Science and Technology 2023BR038 (LX).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer-reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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