Toll-like receptor 3 expressing tumor parenchyma and infiltrating natural killer cells in hepatocellular carcinoma patients.
Toll-like receptor 3 expressing tumor parenchyma and infiltrating natural killer cells in hepatocellular carcinoma patients.
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DOI：
10.1093/jnci/djs436
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发表时间：
2012-12-05
期刊：
影响因子：
--
通讯作者：
Abastado JP
中科院分区：
文献类型：
--
作者：
Chew V;Tow C;Huang C;Bard-Chapeau E;Copeland NG;Jenkins NA;Weber A;Lim KH;Toh HC;Heikenwalder M;Ng IO;Nardin A;Abastado JP
肝细胞癌（HCC）是一种高度侵袭性的癌症，与慢性肝脏炎症失调有关。然而，适当的免疫反应可以控制 HCC 的进展。在这里，我们研究了 Toll 样受体 3 (TLR3) 在 HCC 中的作用和潜在机制。用 TLR3 配体聚 (I:C) 处理后，在体外评估 HCC 细胞死亡、自然杀伤 (NK) 细胞活化和细胞毒性。在自发性肝肿瘤小鼠模型和移植性肿瘤小鼠模型（每组 n = 3-9 只小鼠）中研究了 TLR3 对肿瘤实质和浸润免疫细胞的影响。使用免疫组织化学和定量聚合酶链反应分析 172 名 HCC 患者的肿瘤样本。使用配对 t 检验和方差分析检验来计算 P 值。 TLR3 表达与生存之间的关系通过 Kaplan-Meier 单变量生存分析和对数秩检验确定。所有统计检验都是双面的。在体外，TLR3 激活增加了 TLR3+ SNU182 HCC 细胞系的细胞死亡（30.5% vs 8.5%，P = .03），并促进 NK 细胞激活（32.6% vs 19.4%，P < .001）和细胞毒性（相对增加四倍，P = .03）。在体内，Poly(I:C) 治疗可增加肿瘤内趋化因子表达、NK 细胞活化和肿瘤浸润，以及肿瘤浸润 T 和 NK 细胞的增殖。肿瘤实质细胞增殖减少。此外，趋化因子的表达或聚（I:C）治疗可减少肿瘤生长。患者样本中的 TLR3 表达与 NK 细胞活化、NK 和 T 细胞肿瘤浸润相关，并与肿瘤实质细胞活力呈负相关。 TLR3 表达还与 HCC 患者的较长生存期相关（生存风险比 = 2.1，95% 置信区间 = 1.3 至 3.4，P = .002）。 TLR3 是 HCC 进展的重要调节剂，也是新型免疫疗法的潜在靶点。
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. 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. 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). TLR3 is an important modulator of HCC progression and is a potential target for novel immunotherapy.
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影响因子：
24.5
作者：
Chew V;Chen J;Lee D;Loh E;Lee J;Lim KH;Weber A;Slankamenac K;Poon RT;Yang H;Ooi LL;Toh HC;Heikenwalder M;Ng IO;Nardin A;Abastado JP
通讯作者：
Abastado JP
影响因子：
4.4
作者：
Salaun, Bruno;Coste, Isabelle;Renno, Toufic
通讯作者：
Renno, Toufic
影响因子：
64.5
作者：
CHISARI, FV;KLOPCHIN, K;PALMITER, RD
通讯作者：
PALMITER, RD
影响因子：
64.8
作者：
Schulz, O;Diebold, SS;Sousa, CRE
通讯作者：
Sousa, CRE
影响因子：
46.9
作者：
Keng, Vincent W.;Villanueva, Augusto;Chiang, Derek Y.;Dupuy, Adam J.;Ryan, Barbara J.;Matise, Ilze;Silverstein, Kevin A. T.;Sarver, Aaron;Starr, Timothy K.;Akagi, Keiko;Tessarollo, Lino;Collier, Lara S.;Powers, Scott;Lowe, Scott W.;Jenkins, Nancy A.;Copeland, Neal G.;Llovet, Josep M.;Largaespada, David A.
通讯作者：
Largaespada, David A.