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Gut. 2018 May;67(5):931-944. doi: 10.1136/gutjnl-2017-314032. Epub 2017 Sep 22.

Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy.

Author information

1
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
2
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
3
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
4
Department of Surgery, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
5
Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, Hong Kong.
6
Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA.
7
AIDS Institute, The University of Hong Kong, Hong Kong, Hong Kong.
8
Department 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
State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong.

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.

KEYWORDS:

Cellular Immunology; Hepatocellular Carcinoma; Immunotherapy

PMID:
28939663
PMCID:
PMC5961939
DOI:
10.1136/gutjnl-2017-314032
[Indexed for MEDLINE]
Free PMC Article

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