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Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma
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 requ...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Group
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273680/ https://www.ncbi.nlm.nih.gov/pubmed/21930732 http://dx.doi.org/10.1136/gutjnl-2011-300509 |
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author | Chew, Valerie Chen, Jinmiao Lee, Deming Loh, Evelyn Lee, Joyce Lim, Kiat Hon Weber, Achim Slankamenac, Ksenija Poon, Ronnie T P Yang, Henry Ooi, London Lucien P J Toh, Han Chong Heikenwalder, Mathias Ng, Irene O L Nardin, Alessandra Abastado, Jean-Pierre |
author_facet | Chew, Valerie Chen, Jinmiao Lee, Deming Loh, Evelyn Lee, Joyce Lim, Kiat Hon Weber, Achim Slankamenac, Ksenija Poon, Ronnie T P Yang, Henry Ooi, London Lucien P J Toh, Han Chong Heikenwalder, Mathias Ng, Irene O L Nardin, Alessandra Abastado, Jean-Pierre |
author_sort | Chew, Valerie |
collection | PubMed |
description | 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 nearest-template 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. |
format | Online Article Text |
id | pubmed-3273680 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | BMJ Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-32736802012-02-16 Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma Chew, Valerie Chen, Jinmiao Lee, Deming Loh, Evelyn Lee, Joyce Lim, Kiat Hon Weber, Achim Slankamenac, Ksenija Poon, Ronnie T P Yang, Henry Ooi, London Lucien P J Toh, Han Chong Heikenwalder, Mathias Ng, Irene O L Nardin, Alessandra Abastado, Jean-Pierre Gut Hepatology 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 nearest-template 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. BMJ Group 2011-09-19 2012-03 /pmc/articles/PMC3273680/ /pubmed/21930732 http://dx.doi.org/10.1136/gutjnl-2011-300509 Text en © 2012, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode. |
spellingShingle | Hepatology Chew, Valerie Chen, Jinmiao Lee, Deming Loh, Evelyn Lee, Joyce Lim, Kiat Hon Weber, Achim Slankamenac, Ksenija Poon, Ronnie T P Yang, Henry Ooi, London Lucien P J Toh, Han Chong Heikenwalder, Mathias Ng, Irene O L Nardin, Alessandra Abastado, Jean-Pierre Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma |
title | Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma |
title_full | Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma |
title_fullStr | Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma |
title_full_unstemmed | Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma |
title_short | Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma |
title_sort | chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma |
topic | Hepatology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273680/ https://www.ncbi.nlm.nih.gov/pubmed/21930732 http://dx.doi.org/10.1136/gutjnl-2011-300509 |
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