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Article: Chemokine-driven lymphocyte infiltration: An early intratumoural event determining long-term survival in resectable hepatocellular carcinoma
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TitleChemokine-driven lymphocyte infiltration: An early intratumoural event determining long-term survival in resectable hepatocellular carcinoma
 
AuthorsChew, V7
Chen, J7
Lee, D7
Loh, E7
Lee, J2 2
Lim, KH1
Weber, A5
Slankamenac, K5
Poon, RTP2 2
Yang, H7
Ooi, LLPJ3 1
Toh, HC3
Heikenwalder, M4 8 6
Ng, IOL2 2
Nardin, A7
Abastado, JP7
 
Issue Date2012
 
PublisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
 
CitationGut, 2012, v. 61 n. 3, p. 427-438 [How to Cite?]
DOI: http://dx.doi.org/10.1136/gutjnl-2011-300509
 
AbstractObjective: Hepatocellular carcinoma (HCC) is a heterogeneous disease with poor prognosis and limited methods for predicting patient survival. The nature of the immune cells that infiltrate tumours is known to impact clinical outcome. However, the molecular events that regulate this infiltration require further understanding. Here the ability of immune genes expressed in the tumour microenvironment to predict disease progression was investigated. Methods: Using quantitative PCR, the expression of 14 immune genes in resected tumour tissues from 57 Singaporean patients was analysed. The nearesttemplate prediction method was used to derive and test a prognostic signature from this training cohort. The signature was then validated in an independent cohort of 98 patients from Hong Kong and Zurich. Intratumoural components expressing these critical immune genes were identified by in situ labelling. Regulation of these genes was analysed in vitro using the HCC cell line SNU-182. Results: The identified 14 immune-gene signature predicts patient survival in both the training cohort (p=0.0004 and HR=5.2) and the validation cohort (p=0.0051 and HR=2.5) irrespective of patient ethnicity and disease aetiology. Importantly, it predicts the survival of patients with early disease (stages I and II), for whom classical clinical parameters provide limited information. The lack of predictive power in late disease stages III and IV emphasises that a protective immune microenvironment has to be established early in order to impact disease progression significantly. This signature includes the chemokine genes CXCL10, CCL5 and CCL2, whose expression correlates with markers of T helper 1 (Th1), CD8 + T and natural killer (NK) cells. Inflammatory cytokines (tumour necrosis factor α, interferon γ) and Toll-like receptor 3 ligands stimulate intratumoural production of these chemokines which drive tumour infiltration by T and NK cells, leading to enhanced cancer cell death. Conclusion: A 14 immune-gene signature, which identifies molecular cues driving tumour infiltration by lymphocytes, accurately predicts survival of patients with HCC especially in early disease.
 
ISSN0017-5749
2012 Impact Factor: 10.732
2012 SCImago Journal Rankings: 3.379
 
DOIhttp://dx.doi.org/10.1136/gutjnl-2011-300509
 
PubMed Central IDPMC3273680
 
ISI Accession Number IDWOS:000300058500015
Funding AgencyGrant Number
Biomedical Sciences Institutes (BMSI)
Agency for Science, Technology and Research (A*STAR)
Hong Kong Research Grants CouncilHKU 7/CRG/09
Funding Information:

This study was mainly funded by The Biomedical Sciences Institutes (BMSI), Agency for Science, Technology and Research (A*STAR), and partly funded by a Hong Kong Research Grants Council Collaborative Research Grant to IOLN (HKU 7/CRG/09).

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorChew, V
 
dc.contributor.authorChen, J
 
dc.contributor.authorLee, D
 
dc.contributor.authorLoh, E
 
dc.contributor.authorLee, J
 
dc.contributor.authorLim, KH
 
dc.contributor.authorWeber, A
 
dc.contributor.authorSlankamenac, K
 
dc.contributor.authorPoon, RTP
 
dc.contributor.authorYang, H
 
dc.contributor.authorOoi, LLPJ
 
dc.contributor.authorToh, HC
 
dc.contributor.authorHeikenwalder, M
 
dc.contributor.authorNg, IOL
 
dc.contributor.authorNardin, A
 
dc.contributor.authorAbastado, JP
 
dc.date.accessioned2011-12-21T08:56:18Z
 
dc.date.available2011-12-21T08:56:18Z
 
dc.date.issued2012
 
dc.description.abstractObjective: Hepatocellular carcinoma (HCC) is a heterogeneous disease with poor prognosis and limited methods for predicting patient survival. The nature of the immune cells that infiltrate tumours is known to impact clinical outcome. However, the molecular events that regulate this infiltration require further understanding. Here the ability of immune genes expressed in the tumour microenvironment to predict disease progression was investigated. Methods: Using quantitative PCR, the expression of 14 immune genes in resected tumour tissues from 57 Singaporean patients was analysed. The nearesttemplate prediction method was used to derive and test a prognostic signature from this training cohort. The signature was then validated in an independent cohort of 98 patients from Hong Kong and Zurich. Intratumoural components expressing these critical immune genes were identified by in situ labelling. Regulation of these genes was analysed in vitro using the HCC cell line SNU-182. Results: The identified 14 immune-gene signature predicts patient survival in both the training cohort (p=0.0004 and HR=5.2) and the validation cohort (p=0.0051 and HR=2.5) irrespective of patient ethnicity and disease aetiology. Importantly, it predicts the survival of patients with early disease (stages I and II), for whom classical clinical parameters provide limited information. The lack of predictive power in late disease stages III and IV emphasises that a protective immune microenvironment has to be established early in order to impact disease progression significantly. This signature includes the chemokine genes CXCL10, CCL5 and CCL2, whose expression correlates with markers of T helper 1 (Th1), CD8 + T and natural killer (NK) cells. Inflammatory cytokines (tumour necrosis factor α, interferon γ) and Toll-like receptor 3 ligands stimulate intratumoural production of these chemokines which drive tumour infiltration by T and NK cells, leading to enhanced cancer cell death. Conclusion: A 14 immune-gene signature, which identifies molecular cues driving tumour infiltration by lymphocytes, accurately predicts survival of patients with HCC especially in early disease.
 
dc.description.naturepublished_or_final_version
 
dc.identifier.citationGut, 2012, v. 61 n. 3, p. 427-438 [How to Cite?]
DOI: http://dx.doi.org/10.1136/gutjnl-2011-300509
 
dc.identifier.doihttp://dx.doi.org/10.1136/gutjnl-2011-300509
 
dc.identifier.epage438
 
dc.identifier.hkuros197825
 
dc.identifier.isiWOS:000300058500015
Funding AgencyGrant Number
Biomedical Sciences Institutes (BMSI)
Agency for Science, Technology and Research (A*STAR)
Hong Kong Research Grants CouncilHKU 7/CRG/09
Funding Information:

This study was mainly funded by The Biomedical Sciences Institutes (BMSI), Agency for Science, Technology and Research (A*STAR), and partly funded by a Hong Kong Research Grants Council Collaborative Research Grant to IOLN (HKU 7/CRG/09).

 
dc.identifier.issn0017-5749
2012 Impact Factor: 10.732
2012 SCImago Journal Rankings: 3.379
 
dc.identifier.issue3
 
dc.identifier.pmcidPMC3273680
 
dc.identifier.pmid21930732
 
dc.identifier.scopuseid_2-s2.0-84857050018
 
dc.identifier.spage427
 
dc.identifier.urihttp://hdl.handle.net/10722/143800
 
dc.identifier.volume61
 
dc.languageeng
 
dc.publisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofGut
 
dc.relation.referencesReferences in Scopus
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
dc.rightsUnlocked article acknowledgement: This article has been accepted for publication in Gut, 2011, v. 61 n. 3, p. 427-438 following peer review and can also be viewed on the journal’s website at http://gut.bmj.com
 
dc.titleChemokine-driven lymphocyte infiltration: An early intratumoural event determining long-term survival in resectable hepatocellular carcinoma
 
dc.typeArticle
 
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<description.abstract>Objective: Hepatocellular carcinoma (HCC) is a heterogeneous disease with poor prognosis and limited methods for predicting patient survival. The nature of the immune cells that infiltrate tumours is known to impact clinical outcome. However, the molecular events that regulate this infiltration require further understanding. Here the ability of immune genes expressed in the tumour microenvironment to predict disease progression was investigated. Methods: Using quantitative PCR, the expression of 14 immune genes in resected tumour tissues from 57 Singaporean patients was analysed. The nearesttemplate prediction method was used to derive and test a prognostic signature from this training cohort. The signature was then validated in an independent cohort of 98 patients from Hong Kong and Zurich. Intratumoural components expressing these critical immune genes were identified by in situ labelling. Regulation of these genes was analysed in vitro using the HCC cell line SNU-182. Results: The identified 14 immune-gene signature predicts patient survival in both the training cohort (p=0.0004 and HR=5.2) and the validation cohort (p=0.0051 and HR=2.5) irrespective of patient ethnicity and disease aetiology. Importantly, it predicts the survival of patients with early disease (stages I and II), for whom classical clinical parameters provide limited information. The lack of predictive power in late disease stages III and IV emphasises that a protective immune microenvironment has to be established early in order to impact disease progression significantly. This signature includes the chemokine genes CXCL10, CCL5 and CCL2, whose expression correlates with markers of T helper 1 (Th1), CD8 + T and natural killer (NK) cells. Inflammatory cytokines (tumour necrosis factor &#945;, interferon &#947;) and Toll-like receptor 3 ligands stimulate intratumoural production of these chemokines which drive tumour infiltration by T and NK cells, leading to enhanced cancer cell death. Conclusion: A 14 immune-gene signature, which identifies molecular cues driving tumour infiltration by lymphocytes, accurately predicts survival of patients with HCC especially in early disease.</description.abstract>
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Author Affiliations
  1. Singapore General Hospital
  2. The University of Hong Kong
  3. National Cancer Centre, Singapore
  4. University Hospital Zurich Institute of Neuropathology
  5. UniversitatsSpital Zurich
  6. null
  7. Agency for Science, Technology and Research, Singapore
  8. Technische Universität München