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: José Medina-Echeverz[Show abstract] [Hide abstract]
ABSTRACT: Immunosuppressive CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) accumulate in the livers of tumor-bearing mice. We studied hepatic MDSCs in two murine models of immune mediated hepatitis. Unexpectedly, treatment of tumor bearing mice with Concanavalin A or α-Galactosylceramide resulted in increased ALT and AST serum levels in comparison to tumor free mice. Adoptive transfer of hepatic MDSCs into naïve mice exacerbated Concanavalin A induced liver damage. Hepatic CD11b+Gr-1+ cells revealed a polarized pro-inflammatory gene signature after Concanavalin A treatment. An IFN-γ-dependent up regulation of CD40 on hepatic CD11b+Gr-1+ cells along with an up regulation of CD80, CD86, and CD1d after Concanavalin A treatment was observed. Concanavalin A treatment resulted in a loss of suppressor function by tumor-induced CD11b+Gr-1+ MDSCs as well as enhanced reactive oxygen species-mediated hepatotoxicity. CD40 knockdown in hepatic MDSCs led to increased arginase activity upon Concanavalin A treatment and lower ALT/AST serum levels. Finally, blockade of arginase activity in Cd40−/− tumor-induced myeloid cells resulted in exacerbation of hepatitis and increased reactive oxygen species production in vivo. Our findings indicate that in a setting of acute hepatitis, tumor-induced hepatic MDSCs act as pro-inflammatory immune effector cells capable of killing hepatocytes in a CD40-dependent manner.This article is protected by copyright. All rights reservedEuropean Journal of Immunology 01/2015; 45(4). DOI:10.1002/eji.201445093 · 4.52 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
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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