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Article: Chemokine-driven lymphocyte infiltration: An early intratumoural event determining long-term survival in resectable hepatocellular carcinoma

TitleChemokine-driven lymphocyte infiltration: An early intratumoural event determining long-term survival in resectable hepatocellular carcinoma
Authors
Issue Date2012
PublisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
Citation
Gut, 2012, v. 61 n. 3, p. 427-438 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/143800
ISSN
2015 Impact Factor: 14.921
2015 SCImago Journal Rankings: 6.474
PubMed Central ID
ISI Accession Number ID
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).

References

 

DC FieldValueLanguage
dc.contributor.authorChew, Ven_HK
dc.contributor.authorChen, Jen_HK
dc.contributor.authorLee, Den_HK
dc.contributor.authorLoh, Een_HK
dc.contributor.authorLee, Jen_HK
dc.contributor.authorLim, KHen_HK
dc.contributor.authorWeber, Aen_HK
dc.contributor.authorSlankamenac, Ken_HK
dc.contributor.authorPoon, RTPen_HK
dc.contributor.authorYang, Hen_HK
dc.contributor.authorOoi, LLPJen_HK
dc.contributor.authorToh, HCen_HK
dc.contributor.authorHeikenwalder, Men_HK
dc.contributor.authorNg, IOLen_HK
dc.contributor.authorNardin, Aen_HK
dc.contributor.authorAbastado, JPen_HK
dc.date.accessioned2011-12-21T08:56:18Z-
dc.date.available2011-12-21T08:56:18Z-
dc.date.issued2012en_HK
dc.identifier.citationGut, 2012, v. 61 n. 3, p. 427-438en_HK
dc.identifier.issn0017-5749en_HK
dc.identifier.urihttp://hdl.handle.net/10722/143800-
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.en_HK
dc.languageengen_US
dc.publisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/en_HK
dc.relation.ispartofGuten_HK
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 carcinomaen_HK
dc.typeArticleen_HK
dc.identifier.emailPoon, RTP: poontp@hkucc.hku.hken_HK
dc.identifier.emailNg, IOL: iolng@hkucc.hku.hken_HK
dc.identifier.authorityPoon, RTP=rp00446en_HK
dc.identifier.authorityNg, IOL=rp00335en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1136/gutjnl-2011-300509en_HK
dc.identifier.pmid21930732-
dc.identifier.pmcidPMC3273680-
dc.identifier.scopuseid_2-s2.0-84857050018en_HK
dc.identifier.hkuros197825en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84857050018&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume61en_HK
dc.identifier.issue3en_HK
dc.identifier.spage427en_HK
dc.identifier.epage438en_HK
dc.identifier.isiWOS:000300058500015-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridChew, V=33567510900en_HK
dc.identifier.scopusauthoridChen, J=50461020700en_HK
dc.identifier.scopusauthoridLee, D=50461872800en_HK
dc.identifier.scopusauthoridLoh, E=50461751400en_HK
dc.identifier.scopusauthoridLee, J=37031441700en_HK
dc.identifier.scopusauthoridLim, KH=14119927300en_HK
dc.identifier.scopusauthoridWeber, A=9943458100en_HK
dc.identifier.scopusauthoridSlankamenac, K=6504049312en_HK
dc.identifier.scopusauthoridPoon, RTP=7103097223en_HK
dc.identifier.scopusauthoridYang, H=23468238300en_HK
dc.identifier.scopusauthoridOoi, LLPJ=16245598100en_HK
dc.identifier.scopusauthoridToh, HC=7006272192en_HK
dc.identifier.scopusauthoridHeikenwalder, M=6602267435en_HK
dc.identifier.scopusauthoridNg, IOL=7102753722en_HK
dc.identifier.scopusauthoridNardin, A=33567983300en_HK
dc.identifier.scopusauthoridAbastado, JP=35965948900en_HK

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