File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

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

TitleHepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy
Authors
KeywordsCellular Immunology
Hepatocellular Carcinoma
Immunotherapy
Issue Date2018
PublisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
Citation
Gut, 2018, v. 67 n. 5, p. 931-944 How to Cite?
AbstractObjective: 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. © 2018 Article author(s).
Persistent Identifierhttp://hdl.handle.net/10722/273974
ISSN
2017 Impact Factor: 17.016
2015 SCImago Journal Rankings: 6.474
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZhou, J-
dc.contributor.authorLiu, M-
dc.contributor.authorSun, H-
dc.contributor.authorFeng, Y-
dc.contributor.authorXu, L-
dc.contributor.authorChan, AWH-
dc.contributor.authorTong, JH-
dc.contributor.authorWong, J-
dc.contributor.authorChong, CCN-
dc.contributor.authorLai, PBS-
dc.contributor.authorWang, HKS-
dc.contributor.authorTsang, SW-
dc.contributor.authorGoodwin, T-
dc.contributor.authorLiu, R-
dc.contributor.authorHuang, L-
dc.contributor.authorChen, Z-
dc.contributor.authorSung, JJ-
dc.contributor.authorChow, KL-
dc.contributor.authorTo, KF-
dc.contributor.authorCheng, ASL-
dc.date.accessioned2019-08-18T14:52:30Z-
dc.date.available2019-08-18T14:52:30Z-
dc.date.issued2018-
dc.identifier.citationGut, 2018, v. 67 n. 5, p. 931-944-
dc.identifier.issn0017-5749-
dc.identifier.urihttp://hdl.handle.net/10722/273974-
dc.description.abstractObjective: 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. © 2018 Article author(s).-
dc.languageeng-
dc.publisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/-
dc.relation.ispartofGut-
dc.rightsGut. Copyright © BMJ Publishing Group.-
dc.rightsThis article has been accepted for publication in [Journal, Year] following peer review, and the Version of Record can be accessed online at [insert full DOI eg. http://dx.doi.org/10.1136/xxxxx]. [© Authors (or their employer(s)) OR © BMJ Publishing Group Ltd ( for assignments of BMJ Case Reports)] <year>-
dc.subjectCellular Immunology-
dc.subjectHepatocellular Carcinoma-
dc.subjectImmunotherapy-
dc.titleHepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy-
dc.typeArticle-
dc.identifier.emailChen, Z: zchenai@hku.hk-
dc.identifier.authorityChen, Z=rp00243-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1136/gutjnl-2017-314032-
dc.identifier.pmid28939663-
dc.identifier.scopuseid_2-s2.0-85046457749-
dc.identifier.hkuros301451-
dc.identifier.volume67-
dc.identifier.issue5-
dc.identifier.spage931-
dc.identifier.epage944-
dc.identifier.isiWOS:000429733600017-
dc.publisher.placeUnited Kingdom-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats