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.
SourceAvailable from: Yan Shao[Show abstract] [Hide abstract]
ABSTRACT: Human hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide with a poor prognosis of limited survival. The role of regulatory B cell (Breg), a new important B cell subset, in HCC progression remains unclear. We firstly found that the percentage of B cells at tumor margin was significantly higher than that in tumor and non-tumor region. Especially, increased intrahepatic B cells at tumor margin were positively associated with tumor invasive features and more tumor recurrence. Besides, HCC patients had a significantly higher percentage of circulating Bregs than healthy people. Increased circulating Bregs were correlated with advanced tumor staging, tumor multiplicity and venous infiltration. Next, we firstly revealed that human Bregs promoted HCC tumor growth independent of Tregs in SCID mice. The migration of Bregs from blood into tumor was also confirmed in mice. Finally, we further explored the molecular mechanism of Bregs promoting proliferation and migration of HCC cells in vitro. Bregs promoted HCC growth and invasiveness by direct interacting with liver cancer cells through CD40/CD154 signaling pathway.Cancer Letters 10/2014; 355(2). DOI:10.1016/j.canlet.2014.09.026 · 5.02 Impact Factor
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ABSTRACT: Molecular factors driving immune-mediated inflammation in the liver are incompletely understood. The transcription factor cyclic AMP responsive element modulator-alpha (CREMα) can endorse differentiation of T lymphocytes towards Th17 cells, thereby promoting autoimmunity in systemic lupus erythematosus or lung inflammation. To investigate the role of CREMα in liver disease we subjected transgenic mice overexpressing CREMα under control of the CD2 promoter (crem(tg) mice), which restrains expression mainly to lymphocytes (T, NK, NKT cells), to acute and chronic liver injury models. Already in steady state, transgenic CREMα overexpression broadly reduced hepatic immune cell numbers by decreasing their viability, but did not affect immune cell migration or the fibrogenic response to chronic liver injury. Strikingly, crem(tg) mice developed more severe immune-mediated hepatitis with higher mortality rate compared to wildtype (wt) mice upon Concanavalin A (ConA) administration. Unlike in T cells from spleen, CREMα-overexpression did not induce a predominant Th17 response in intrahepatic T-cells, as hepatic crem(tg) CD4+ T-cells expressed less IL-17 than wt T-cells. Reconstitution of Rag1(/-) mice with Crem(-/-) T-cells did not ameliorate ConA hepatitis. Overexpression of CREMα did not influence NK and NKT-cell effector functions either. Interestingly, a subset of monocytic myeloid derived suppressor cells (MDSC) also expressed CD2 and CREMα. Crem(tg) MDSC isolated from liver expressed reduced iNOS and Arginase-1 and displayed a reduced T-cell suppressive activity. The adoptive transfer of wt MDSC was capable of reducing the fulminant immune-mediated liver damage in crem(tg) mice to wt level. Conclusion: Thus, our results suggest compartmental differences of T-cell activation pathways between liver and other organs in autoimmunity and define a functional role of CREMα in hepatic monocytic MDSC for the pathogenesis of immune-mediated liver disease. (Hepatology 2014;).Hepatology 03/2015; 61(3). DOI:10.1002/hep.27571 · 11.19 Impact Factor
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ABSTRACT: In contrast to a majority of cancer types, the initiation of hepatocellular carcinoma (HCC) is intimately associated with a chronically diseased liver tissue, with one of the most prevalent etiological factors being hepatitis B virus (HBV). Transformation of the liver in HBV-associated HCC often follows from or accompanies long-term symptoms of chronic hepatitis, inflammation and cirrhosis, and viral load is a strong predictor for both incidence and progression of HCC. Besides aiding in transformation, HBV plays a crucial role in modulating the accumulation and activation of both cellular components of the microenvironment, such as immune cells and fibroblasts, and non-cellular components of the microenvironment, such as cytokines and growth factors, markedly influencing disease progression and prognosis. This review will explore some of these components and mechanisms to demonstrate both underlying themes and the inherent complexity of these interacting systems in the initiation, progression, and metastasis of HBV-positive HCC.07/2014; 1(3):396-412. DOI:10.1093/nsr/nwu038