TY - JOUR
T1 - Toll-like receptor 3 expressing tumor parenchyma and infiltrating natural killer cells in hepatocellular carcinoma patients
AU - Chew, Valerie
AU - Tow, Charlene
AU - Huang, Caleb
AU - Bard-Chapeau, Emilie
AU - Copeland, Neal G.
AU - Jenkins, Nancy A.
AU - Weber, Achim
AU - Lim, Kiat Hon
AU - Toh, Han Chong
AU - Heikenwalder, Mathias
AU - Ng, Irene Oi Lin
AU - Nardin, Alessandra
AU - Abastado, Jean Pierre
N1 - Funding Information:
This research was funded by Singapore Immunology Network (SIgN) of the Biomedical Research Council, A*STAR, Singapore. This study was partly funded by a Hong Kong Research Grants Council Collaborative Research Grant (HKU 7/CRG/09 to IOLN). Mathias Heikenwalder was funded by a European Research Council starting grant.
PY - 2012/12
Y1 - 2012/12
N2 - Background: Hepatocellular carcinoma (HCC) is a highly aggressive cancer that is linked to chronically dysregulated liver inflammation. However, appropriate immune responses can control HCC progression. Here we investigated the role and underlying mechanism of toll-like receptor 3 (TLR3) in HCC. Methods: HCC cell death, and natural killer (NK) cell activation and cytotoxicity were assessed in vitro after treatment with the TLR3 ligand poly(I:C). The effect of TLR3 on the tumor parenchyma and infiltrating immune cells was investigated in a spontaneous liver tumor mouse model and a transplanted tumor mouse model (n 3-9 mice per group). Immunohistochemistry and quantitative polymerase chain reaction were used to analyze tumor samples from 172 HCC patients. Paired t-tests and analysis of variance tests were used to calculate P-values. The relationship between TLR3 expression and survival was determined by the Kaplan-Meier univariate survival analysis and a log-rank test. All statistical tests were two-sided. Results: TLR3 activation increased cell death in the TLR3 SNU182 HCC cell line (30.5% vs 8.5%, P = .03) and promoted NK-cell activation (32.6% vs 19.4%, P < .001) and cytotoxicity (relative fourfold increase, P = .03) in vitro. In vivo, poly(I:C) treatment increased intratumoral chemokine expression, NK-cell activation and tumor infiltration, and proliferation of tumor-infiltrating T and NK cells. Proliferation of tumor parenchyma cells was decreased. Also, expression of chemokines or treatment with poly(I:C) decreased tumor growth. TLR3 expression in patient samples correlated with NK-cell activation, NK- and T-cell tumor infiltration, and inversely correlated with tumor parenchyma cell viability. TLR3 expression was also associated with longer survival in HCC patients (hazard ratio of survival = 2.1, 95% confidence interval = 1.3 to 3.4, P = .002). Conclusions: TLR3 is an important modulator of HCC progression and is a potential target for novel immunotherapy.
AB - Background: Hepatocellular carcinoma (HCC) is a highly aggressive cancer that is linked to chronically dysregulated liver inflammation. However, appropriate immune responses can control HCC progression. Here we investigated the role and underlying mechanism of toll-like receptor 3 (TLR3) in HCC. Methods: HCC cell death, and natural killer (NK) cell activation and cytotoxicity were assessed in vitro after treatment with the TLR3 ligand poly(I:C). The effect of TLR3 on the tumor parenchyma and infiltrating immune cells was investigated in a spontaneous liver tumor mouse model and a transplanted tumor mouse model (n 3-9 mice per group). Immunohistochemistry and quantitative polymerase chain reaction were used to analyze tumor samples from 172 HCC patients. Paired t-tests and analysis of variance tests were used to calculate P-values. The relationship between TLR3 expression and survival was determined by the Kaplan-Meier univariate survival analysis and a log-rank test. All statistical tests were two-sided. Results: TLR3 activation increased cell death in the TLR3 SNU182 HCC cell line (30.5% vs 8.5%, P = .03) and promoted NK-cell activation (32.6% vs 19.4%, P < .001) and cytotoxicity (relative fourfold increase, P = .03) in vitro. In vivo, poly(I:C) treatment increased intratumoral chemokine expression, NK-cell activation and tumor infiltration, and proliferation of tumor-infiltrating T and NK cells. Proliferation of tumor parenchyma cells was decreased. Also, expression of chemokines or treatment with poly(I:C) decreased tumor growth. TLR3 expression in patient samples correlated with NK-cell activation, NK- and T-cell tumor infiltration, and inversely correlated with tumor parenchyma cell viability. TLR3 expression was also associated with longer survival in HCC patients (hazard ratio of survival = 2.1, 95% confidence interval = 1.3 to 3.4, P = .002). Conclusions: TLR3 is an important modulator of HCC progression and is a potential target for novel immunotherapy.
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U2 - 10.1093/jnci/djs436
DO - 10.1093/jnci/djs436
M3 - Article
C2 - 23197495
AN - SCOPUS:84870915632
SN - 0027-8874
VL - 104
SP - 1796
EP - 1807
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 23
ER -