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Article: Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma

TitleTargeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma
Authors
Keywordscancer immunobiology
fibrosis
hepatocellular carcinoma
immunotherapy
liver immunology
Issue Date2019
PublisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
Citation
Gut, 2019 How to Cite?
AbstractObjective: 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. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
Persistent Identifierhttp://hdl.handle.net/10722/273977
ISSN
2019 Impact Factor: 19.819
2015 SCImago Journal Rankings: 6.474
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLiu, M-
dc.contributor.authorZhou, J-
dc.contributor.authorLiu, X-
dc.contributor.authorFeng, Y-
dc.contributor.authorYang, W-
dc.contributor.authorWu, F-
dc.contributor.authorCheung, OKW-
dc.contributor.authorSun, H-
dc.contributor.authorZeng, X-
dc.contributor.authorTang, W-
dc.contributor.authorMok, MTS-
dc.contributor.authorWong, J-
dc.contributor.authorYeung, PC-
dc.contributor.authorChen, Z-
dc.contributor.authorLai, PBS-
dc.contributor.authorJin, H-
dc.contributor.authorChen, J-
dc.contributor.authorChan, SL-
dc.contributor.authorChan, AWH-
dc.contributor.authorTo, KF-
dc.contributor.authorSung, JJ-
dc.contributor.authorChen, M-
dc.contributor.authorCheng, ASL-
dc.date.accessioned2019-08-18T14:52:34Z-
dc.date.available2019-08-18T14:52:34Z-
dc.date.issued2019-
dc.identifier.citationGut, 2019-
dc.identifier.issn0017-5749-
dc.identifier.urihttp://hdl.handle.net/10722/273977-
dc.description.abstractObjective: 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. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.-
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.subjectcancer immunobiology-
dc.subjectfibrosis-
dc.subjecthepatocellular carcinoma-
dc.subjectimmunotherapy-
dc.subjectliver immunology-
dc.titleTargeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma-
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-2018-317257-
dc.identifier.scopuseid_2-s2.0-85065582107-
dc.identifier.hkuros301455-
dc.identifier.spagegutjnl-
dc.identifier.epage2018-
dc.identifier.isiWOS:000472085300005-
dc.publisher.placeUnited Kingdom-

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