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Original Article
Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy
  1. Jingying Zhou1,
  2. Man Liu1,
  3. Hanyong Sun2,
  4. Yu Feng1,
  5. Liangliang Xu1,
  6. Anthony W H Chan3,
  7. Joanna H Tong3,
  8. John Wong4,
  9. Charing Ching Ning Chong4,
  10. Paul B S Lai4,
  11. Hector Kwong-Sang Wang5,
  12. Shun-Wa Tsang5,
  13. Tyler Goodwin6,
  14. Rihe Liu6,
  15. Leaf Huang6,
  16. Zhiwei Chen7,8,
  17. Joseph JY Sung2,9,
  18. King Lau Chow5,
  19. Ka Fai To3,
  20. Alfred Sze-Lok Cheng1,9
  1. 1School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
  2. 2Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
  3. 3Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, Hong Kong
  4. 4Department of Surgery, The Chinese University of Hong Kong, HongKong, Hong Kong
  5. 5Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, Hong Kong
  6. 6Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA
  7. 7AIDS Institute, The University of Hong Kong, Hong Kong, Hong Kong
  8. 8Department of Microbiology and Research Center for Infection and Immunity, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
  9. 9State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong
  1. Correspondence to Professor Alfred Sze-Lok Cheng, School of Biomedical Sciences and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong, China; alfredcheng{at}cuhk.edu.hk

Abstract

Objective Myeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC).

Design Immunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems. Mechanistic studies were also conducted in liver-specific CCRK-inducible transgenic (TG) mice and Hepa1–6 orthotopic HCC models using CRISPR/Cas9-mediated Ccrk depletion and liver-targeted nanoparticles for interleukin (IL) 6 trapping. Tumorigenicity and immunophenotype were assessed on single or combined antiprogrammed death-1-ligand 1 (PD-L1) therapy.

Results Tumour-infiltrating CD11b+CD33+HLA-DR MDSCs from patients with HCC potently inhibited autologous CD8+T cell proliferation. Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) positively correlated with poorer survival rates. Hepatocellular CCRK stimulated immunosuppressive CD11b+CD33+HLA-DR MDSC expansion from human peripheral blood mononuclear cells through upregulating IL-6. Mechanistically, CCRK activated nuclear factor-κB (NF-κB) via enhancer of zeste homolog 2 (EZH2) and facilitated NF-κB-EZH2 co-binding to IL-6 promoter. Hepatic CCRK induction in TG mice activated the EZH2/NF-κB/IL-6 cascade, leading to accumulation of polymorphonuclear (PMN) MDSCs with potent T cell suppressive activity. In contrast, inhibiting tumorous Ccrk or hepatic IL-6 increased interferon γ+tumour necrosis factor-α+CD8+ T cell infiltration and impaired tumorigenicity, which was rescued by restoring PMN-MDSCs. Notably, tumorous Ccrk depletion upregulated PD-L1 expression and increased intratumorous CD8+ T cells, thus enhancing PD-L1 blockade efficacy to eradicate HCC.

Conclusion Our results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.

  • Hepatocellular Carcinoma
  • Immunotherapy
  • Cellular Immunology
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Footnotes

  • Contributors Study concept and design: JZ, AC; acquisition of data: JZ, ML, HS, YF, LX, AWHC, JHT; analysis and interpretation of data: JZ, ML, HS, YF, AWHC, AC; acquisition of patient specimens: AWHC, JW, CC, PL, KFT; drafting of the manuscript: JZ, AC; critical revision of the manuscript: JZ, HW, TG, LH, KLC, AC; obtained funding: JZ, RL, LH, JS, KLC, KFT, AC; administrative, technical or other material support: HW, ST, TG, RL, LH, ZC, JS, KLC, KFT; study supervision: AC.

  • Funding This project is supported by the University Grants Committee through the Collaborative Research Fund C4017-14G, General Research Fund 14120816 and 14102914, the Food and Health Bureau through Heath and Medical Research Fund 03141376, and the Focused Innovations Scheme B 1907309 from the Chinese University of Hong Kong (CUHK). Alfred S.L Cheng is supported by funding from the Young Researcher Award, CUHK. Work at UNC is supported by grants from the National Institute of Health (DK100664, CA198999 and CA157738).

  • Competing interests None declared.

  • Patient consent Parental/guardian consent obtained.

  • Ethics approval Joint CUHK-NTEC Clinical Research Ethics Committee.

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

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