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- Title
Toll-Like Receptor 3 Expressing Tumor Parenchyma and Infiltrating Natural Killer Cells in Hepatocellular Carcinoma Patients.
- Authors
Chew, Valerie; Tow, Charlene; Huang, Caleb; Bard-Chapeau, Emilie; Copeland, Neal G.; Jenkins, Nancy A.; Weber, Achim; Lim, Kiat Hon; Toh, Han Chong; Heikenwalder, Mathias; Ng, Irene Oi-Lin; Nardin, Alessandra; Abastado, Jean-Pierre
- Abstract
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.
- Subjects
LIVER cancer; TOLL-like receptors; CANCER patients; KILLER cells; HEPATITIS; NUCLEAR factor of activated T-cells
- Publication
JNCI: Journal of the National Cancer Institute, 2012, Vol 104, Issue 23, p1796
- ISSN
0027-8874
- Publication type
Article
- DOI
10.1093/jnci/djs436