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Article: Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma.

TitleMultidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma.
Authors
Keywordscancer immunobiology
hepatitis B
hepatocellular carcinoma
immunoregulation
immunotherapy
Issue Date2019
PublisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
Citation
Gut, 2019, v. 68 n. 5, p. 916-927 How to Cite?
AbstractBackground and aims: Chronic inflammation induced by chronic hepatitis B virus (HBV) infection increases the risk of hepatocellular carcinoma (HCC). However, little is known about the immune landscape of HBV-related HCC and its influence on the design of effective cancer immunotherapeutics. Methods: We interrogated the immune microenvironments of HBV-related HCC and non-viral-related HCC using immunohistochemistry and cytometry by time-of-flight (CyTOF). On identifying unique immune subsets enriched in HBV-related HCC, we further interrogated their phenotypes and functions using next-generation sequencing (NGS) and in vitro T-cell proliferation assays. Results: In-depth interrogation of the immune landscapes showed that regulatory T cells (TREG) and CD8+ resident memory T cells (TRM) were enriched in HBV-related HCC, whereas Tim-3+CD8+ T cells and CD244+ natural killer cells were enriched in non-viral-related HCC. NGS of isolated TREG and TRM from HBV-related HCC and non-viral-related HCC identified distinct functional signatures associated with T-cell receptor signalling, T-cell costimulation, antigen presentation and programmed cell death protein 1 (PD-1) signalling. TREG and TRM from HBV-related HCC expressed more PD-1 and were functionally more suppressive and exhausted than those from non-virus-related HCC. Furthermore, immunosuppression by PD-1+ TREG could be reversed with anti-PD-1 blockade. Using multiplexed tissue immunofluorescence, we further demonstrated that TREG and TRM contributed to overall patient survival: TREG were associated with a poor prognosis and TRM were associated with a good prognosis in HCC. Conclusion: We have shown that the HBV-related HCC microenvironment is more immunosuppressive and exhausted than the non-viral-related HCC microenvironment. Such in-depth understanding has important implications in disease management and appropriate application of immunotherapeutics. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Persistent Identifierhttp://hdl.handle.net/10722/274101
ISSN
2017 Impact Factor: 17.016
2015 SCImago Journal Rankings: 6.474
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLim, CJ-
dc.contributor.authorLee, YH-
dc.contributor.authorPan, L-
dc.contributor.authorLai, L-
dc.contributor.authorChua, C-
dc.contributor.authorWasser, M-
dc.contributor.authorLim, TKH-
dc.contributor.authorYeong, J-
dc.contributor.authorToh, HC-
dc.contributor.authorLee, SY-
dc.contributor.authorChan, CY-
dc.contributor.authorGoh, BK-
dc.contributor.authorChung, A-
dc.contributor.authorHeikenwalder, M-
dc.contributor.authorNg, IOL-
dc.contributor.authorChow, P-
dc.contributor.authorAlbani, S-
dc.contributor.authorChew, V-
dc.date.accessioned2019-08-18T14:55:05Z-
dc.date.available2019-08-18T14:55:05Z-
dc.date.issued2019-
dc.identifier.citationGut, 2019, v. 68 n. 5, p. 916-927-
dc.identifier.issn0017-5749-
dc.identifier.urihttp://hdl.handle.net/10722/274101-
dc.description.abstractBackground and aims: Chronic inflammation induced by chronic hepatitis B virus (HBV) infection increases the risk of hepatocellular carcinoma (HCC). However, little is known about the immune landscape of HBV-related HCC and its influence on the design of effective cancer immunotherapeutics. Methods: We interrogated the immune microenvironments of HBV-related HCC and non-viral-related HCC using immunohistochemistry and cytometry by time-of-flight (CyTOF). On identifying unique immune subsets enriched in HBV-related HCC, we further interrogated their phenotypes and functions using next-generation sequencing (NGS) and in vitro T-cell proliferation assays. Results: In-depth interrogation of the immune landscapes showed that regulatory T cells (TREG) and CD8+ resident memory T cells (TRM) were enriched in HBV-related HCC, whereas Tim-3+CD8+ T cells and CD244+ natural killer cells were enriched in non-viral-related HCC. NGS of isolated TREG and TRM from HBV-related HCC and non-viral-related HCC identified distinct functional signatures associated with T-cell receptor signalling, T-cell costimulation, antigen presentation and programmed cell death protein 1 (PD-1) signalling. TREG and TRM from HBV-related HCC expressed more PD-1 and were functionally more suppressive and exhausted than those from non-virus-related HCC. Furthermore, immunosuppression by PD-1+ TREG could be reversed with anti-PD-1 blockade. Using multiplexed tissue immunofluorescence, we further demonstrated that TREG and TRM contributed to overall patient survival: TREG were associated with a poor prognosis and TRM were associated with a good prognosis in HCC. Conclusion: We have shown that the HBV-related HCC microenvironment is more immunosuppressive and exhausted than the non-viral-related HCC microenvironment. Such in-depth understanding has important implications in disease management and appropriate application of immunotherapeutics. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.-
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 work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectcancer immunobiology-
dc.subjecthepatitis B-
dc.subjecthepatocellular carcinoma-
dc.subjectimmunoregulation-
dc.subjectimmunotherapy-
dc.titleMultidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma.-
dc.typeArticle-
dc.identifier.emailNg, IOL: iolng@hku.hk-
dc.identifier.authorityNg, IOL=rp00335-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1136/gutjnl-2018-316510-
dc.identifier.pmid29970455-
dc.identifier.scopuseid_2-s2.0-85049668428-
dc.identifier.hkuros301315-
dc.identifier.volume68-
dc.identifier.issue5-
dc.identifier.spage916-
dc.identifier.epage927-
dc.identifier.isiWOS:000471831400018-
dc.publisher.placeUnited Kingdom-

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