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Original article
Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma
  1. Man Liu1,2,
  2. Jingying Zhou1,
  3. Xiaoyu Liu1,
  4. Yu Feng1,
  5. Weiqin Yang1,
  6. Feng Wu3,
  7. Otto Ka-Wing Cheung1,
  8. Hanyong Sun4,5,
  9. Xuezhen Zeng1,
  10. Wenshu Tang1,
  11. Myth T S Mok1,
  12. John Wong6,
  13. Philip Chun Yeung6,
  14. Paul Bo San Lai6,
  15. Zhiwei Chen7,
  16. Hongchuan Jin8,
  17. Jie Chen2,
  18. Stephen Lam Chan9,
  19. Anthony W H Chan3,
  20. Ka Fai To3,10,
  21. Joseph J Y Sung4,11,
  22. Minhu Chen2,
  23. Alfred Sze-Lok Cheng1,11
  1. 1 School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
  2. 2 Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
  3. 3 Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China
  4. 4 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
  5. 5 Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China, Shanghai, China
  6. 6 Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
  7. 7 AIDS Institute, Department of Microbiology and Research Center for Infection and Immunity, The University of Hong Kong, Hong Kong, China
  8. 8 Labortaory of Cancer Biology, Key Laboratory of Biotherapy in Zhejiang, Sir Runrun Shaw hospital, Medical School of Zhejiang University, Hang Zhou, China
  9. 9 Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China
  10. 10 State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China
  11. 11 State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
  1. Correspondence to Professor Alfred Sze-Lok Cheng, The Chinese University of Hong Kong, Hong Kong, China; alfredcheng{at}cuhk.edu.hk

Abstract

Objective Hepatocellular carcinoma (HCC), mostly developed in fibrotic/cirrhotic liver, exhibits relatively low responsiveness to immune checkpoint blockade (ICB) therapy. As myeloid-derived suppressor cell (MDSC) is pivotal for immunosuppression, we investigated its role and regulation in the fibrotic microenvironment with an aim of developing mechanism-based combination immunotherapy.

Design Functional significance of MDSCs was evaluated by flow cytometry using two orthotopic HCC models in fibrotic liver setting via carbon tetrachloride or high-fat high-carbohydrate diet and verified by clinical specimens. Mechanistic studies were conducted in human hepatic stellate cell (HSC)-peripheral blood mononuclear cell culture systems and fibrotic-HCC patient-derived MDSCs. The efficacy of single or combined therapy with anti-programmed death-1-ligand-1 (anti-PD-L1) and a clinically trialled BET bromodomain inhibitor i-BET762 was determined.

Results Accumulation of monocytic MDSCs (M-MDSCs), but not polymorphonuclear MDSCs, in fibrotic livers significantly correlated with reduced tumour-infiltrating lymphocytes (TILs) and increased tumorigenicity in both mouse models. In human HCCs, the tumour-surrounding fibrotic livers were markedly enriched with M-MDSC, with its surrogate marker CD33 significantly associated with aggressive tumour phenotypes and poor survival rates. Mechanistically, activated HSCs induced monocyte-intrinsic p38 MAPK signalling to trigger enhancer reprogramming for M-MDSC development and immunosuppression. Treatment with p38 MAPK inhibitor abrogated HSC-M-MDSC crosstalk to prevent HCC growth. Concomitant with patient-derived M-MDSC suppression by i-BET762, combined treatment with anti-PD-L1 synergistically enhanced TILs, resulting in tumour eradication and prolonged survival in the fibrotic-HCC mouse model.

Conclusion Our results signify how non-tumour-intrinsic properties in the desmoplastic microenvironment can be exploited to reinstate immunosurveillance, providing readily translatable combination strategies to empower HCC immunotherapy.

  • cancer immunobiology
  • fibrosis
  • hepatocellular carcinoma
  • immunotherapy
  • liver immunology
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Footnotes

  • ML and JZ contributed equally.

  • Contributors Study concept and design: ML, JZ and ASLC; Data acquisition and analysis: ML, JZ, XL, YF, WY, FW, HS, XZ, WT, MTSM, AWHC and ASLC; Bioinformatics analysis: FW and OKWC; Clinical resources: JW, PCY, PBSL, ZC, AWHC and KFT; Writing of manuscript: ML, JZ and ASLC; Critical review of manuscript: ML, JZ, PBSL, HJ, JC, SLC, KFT, ZC, JJYS, MC and ASLC; Supervision: ASLC; Funding acquisition: ML, JZ, ZC, JJYS, MC and ASLC.

  • Funding This project is supported by the University Grants Committee through the Collaborative Research Fund (C4045-18W) and the Theme-based Research Scheme (T11-706/18-N), the Health and Medical Research Fund (16170451), the Terry Fox Foundation, the Focused Innovations Scheme-Scheme B (1907309) from the Chinese University of Hong Kong and the Li Ka Shing Foundation (Canada). Man Liu is supported by the China Post-doctoral International Exchange Program and China Postdoctoral Science Foundation.

  • Competing interests None declared.

  • Ethics approval All animal experiments were approved by the Animal Experimentation Ethics Committee of the Chinese University of Hong Kong (AEEC-CUHK). Studies using human specimen were approved by the Joint CUHK-NTEC Clinical Research Ethics Committee.

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

  • Patient consent for publication Obtained.

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