Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer

Abstract

Background 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. Results 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. Conclusions 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.

C-terminal-truncated hepatitis B virus X protein enhances the development of diethylnitrosamine-induced hepatocellular carcinogenesis

“…5a,c). At this short time after DEN treatment, in agreement with previous data (Schneider et al, 2012), proliferation was essentially observed in nonparenchymal cells. Despite a higher degree of cell proliferation in Ct-HBx-transgenic mice than in either FL-HBxtransgenic or WT mice, no statistical difference was observed (Fig.…”

Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment

“…Combined, the above results illustrate the necessity of the presence of pro-inflammatory Kupffer cells in the liver at the early stages of chemically induced hepatocarcinogenesis. Especially tissue-resident KC, but not recruited monocyte-derived cells, might be needed in the DEN model, since tumor incidence and growth are unaltered in livers of DEN-treated D6-deficient mice, which are heavily infiltrated by monocyte-derived macrophages[170].Once a primary tumor is established, macrophages can further contribute to HCC progression, although the distinction between KC and monocyte-derived macrophages has not been made in most studies. One study reports a reduced presence of KC -defined as CD68 + cells present in the blood space of cancerous tissue or in the sinusoids of noncancerous tissues -in HCC tissue compared to noncancerous tissue from the same livers and a further decrease of intratumoral KC presence as tumor size increases, suggesting…”

Role of chemokine pathways in hepatobiliary cancer

“…Tumor-associated macrophages (TAMs) and T cells have most frequently been reported in promoting liver cancer [76]. Although the former integrate functionally diverse macrophage subpopulations mediating both pro-and anti-tumorigenic activities, myeloid cells in general predominantly exert pro-tumorigenic activities.…”