Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer.
Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer.
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DOI：
10.1136/gutjnl-2011-301116
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发表时间：
2012-12
期刊：
影响因子：
24.5
通讯作者：
Tacke F
中科院分区：
文献类型：
--
作者：
Schneider C;Teufel A;Yevsa T;Staib F;Hohmeyer A;Walenda G;Zimmermann HW;Vucur M;Huss S;Gassler N;Wasmuth HE;Lira SA;Zender L;Luedde T;Trautwein C;Tacke F
肝细胞癌（HCC）是一种典型的炎症相关性癌症，但也可能引起抗肿瘤免疫反应，其意义和潜在机制尚不完全清楚。目的观察二乙基亚硝胺（DEN）肝癌小鼠模型的免疫应答。在C57 BL/6野生型（WT）、趋化因子清除受体D 6缺陷型、B细胞-（Igh 6）、CD 4 T细胞-（MHC-II）和T-/B细胞缺陷型（Rag 1）小鼠之间比较DEN治疗后的肿瘤发展和免疫细胞功能。通过比较来自139个HCC组织的基因阵列结果来测试与人类HCC的相关性。在小鼠中，DEN在24周后诱导癌前病变和在42周后诱导HCC样肿瘤，伴随着肝脏中显著的白细胞浸润和不同的肝内趋化因子（CCL 2，CCL 5，CXCL 9）的上调。巨噬细胞和CD 8（细胞毒性）T细胞最显著地富集在荷瘤肝脏中，类似于来自人HCC的样品。骨髓来源的抑制细胞（MDSC）增加，在肝外隔室DEN治疗的小鼠（骨髓，脾）。免疫细胞亚群对DEN诱导的肝癌发生的贡献进行了功能解剖。在缺乏趋化因子清除受体D 6的D 6 −/−小鼠中，肝脏巨噬细胞浸润显著增加，但肿瘤形成和进展与WT小鼠没有差异。相比之下，DEN治疗后，T-/B细胞缺陷型Rag 1 −/−小鼠的肝肿瘤进展（数量、直径、肿瘤负荷）显著增强。当使用缺乏B细胞（Igh 6 −/−，µMT）或主要组织相容性复合体II的小鼠时，数据表明T细胞阻止初始肿瘤形成，而B细胞严重限制已建立肿瘤的生长。因此，在荷瘤小鼠中，针对肝脏相关模型抗原的抗体产生增强，表明肿瘤相关B细胞活化。一致的是，T和B细胞通路在来自139个人HCC组织的基因阵列分析中受到差异调节，并且与患者的存活率显著相关。 适应性免疫系统的不同轴，也是人类HCC的预后，通过控制肿瘤的形成和进展积极抑制DEN诱导的肝癌发生。
Hepatocellular carcinoma (HCC) is a typical inflammation-associated cancer, but may also provoke antitumour immune responses whose significance and underlying mechanisms are incompletely understood. Objective To characterise immune responses in the diethylnitrosamine (DEN)-liver cancer mouse model. Design Tumour development and immune cell functions upon DEN treatment were compared between C57BL/6 wild-type (WT), chemokine scavenging receptor D6-deficient, B cell- (Igh6), CD4 T cell- (MHC-II) and T-/B cell-deficient (Rag1) mice. Relevance for human HCC was tested by comparing gene array results from 139 HCC tissues. The induction of premalignant lesions after 24 weeks and of HCC-like tumours after 42 weeks by DEN in mice was accompanied by significant leucocyte infiltration in the liver and upregulation of distinct intrahepatic chemokines (CCL2, CCL5, CXCL9). Macrophages and CD8 (cytotoxic) T cells were most prominently enriched in tumour-bearing livers, similar to samples from human HCC. Myeloid-derived suppressor cells (MDSC) increased in extrahepatic compartments of DEN-treated mice (bone marrow, spleen). The contribution of immune cell subsets for DEN-induced hepatocarcinogenesis was functionally dissected. In D6−/− mice, which lack the chemokine scavenging receptor D6, hepatic macrophage infiltration was significantly increased, but tumour formation and progression did not differ from that of WT mice. In contrast, progression of hepatic tumours (numbers, diameters, tumour load) was strikingly enhanced in T-/B cell-deficient Rag1−/− mice upon DEN treatment. When mice deficient for B cells (Igh6−/−, µMT) or major histocompatibility complex II were used, the data indicated that T cells prevent initial tumour formation, while B cells critically limit growth of established tumours. Accordingly, in tumour-bearing mice antibody production against liver-related model antigen was enhanced, indicating tumour-associated B cell activation. In agreement, T and B cell pathways were differentially regulated in gene array analyses from 139 human HCC tissues and significantly associated with patients’ survival. Distinct axes of the adaptive immune system, which are also prognostic in human HCC, actively suppress DEN-induced hepatocarcinogenesis by controlling tumour formation and progression.