Department of Medicine III, University Hospital, RWTH-Aachen, Aachen, Germany.
Gut. 2012 Dec;61(12):1733-43. doi: 10.1136/gutjnl-2011-301116. Epub 2012 Jan 20.
Hepatocellular carcinoma (HCC) is a typical inflammation-associated cancer, but may also provoke antitumour immune responses whose significance and underlying mechanisms are incompletely understood.
To characterise immune responses in the diethylnitrosamine (DEN)-liver cancer mouse model.
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.
肝细胞癌（HCC）是一种典型的炎症相关癌症，但也可能引发抗肿瘤免疫反应，其意义和潜在机制尚不完全清楚。
描述二乙基亚硝胺（DEN）-肝癌小鼠模型中的免疫反应。
比较 C57BL/6 野生型（WT）、趋化因子清除受体 D6 缺陷型、B 细胞（Igh6）、CD4 T 细胞（MHC-II）和 T-/B 细胞缺陷型（Rag1）小鼠在 DEN 处理后肿瘤发展和免疫细胞功能的差异。通过比较 139 例 HCC 组织的基因芯片结果，测试其与人类 HCC 的相关性。
DEN 诱导小鼠 24 周形成癌前病变，42 周形成 HCC 样肿瘤，同时肝脏白细胞浸润明显增加，并上调特定的肝内趋化因子（CCL2、CCL5、CXCL9）。巨噬细胞和 CD8（细胞毒性）T 细胞在荷瘤肝脏中最为丰富，与人类 HCC 样本相似。髓源性抑制细胞（MDSC）在 DEN 处理小鼠的肝外部位（骨髓、脾脏）增加。功能上剖析了免疫细胞亚群对 DEN 诱导的肝癌发生的贡献。在缺乏趋化因子清除受体 D6 的 D6（-/-）小鼠中，肝巨噬细胞浸润明显增加，但肿瘤形成和进展与 WT 小鼠无差异。相比之下，在 DEN 处理的 T-/B 细胞缺陷型 Rag1（-/-）小鼠中，肝肿瘤的进展（数量、直径、肿瘤负荷）显著增强。当使用缺乏 B 细胞（Igh6（-/-）、μMT）或主要组织相容性复合体 II 的小鼠时，数据表明 T 细胞可防止初始肿瘤形成，而 B 细胞则可显著限制已建立的肿瘤生长。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 细胞激活。基因芯片分析 139 例人类 HCC 组织表明，T 和 B 细胞途径存在差异，且与患者的生存显著相关。
适应性免疫系统的不同轴，在人类 HCC 中也具有预后意义，通过控制肿瘤的形成和进展，积极抑制 DEN 诱导的肝癌发生。
