Hepatitis C virus drives the pathogenesis of hepatocellular carcinoma: from immune evasion to carcinogenesis

Abstract

Persistent hepatitis C virus (HCV) infection is associated with high incidence of hepatocellular carcinoma (HCC), the most common primary malignancy of the liver with over half a million new cases diagnosed annually worldwide. The aryl hydrocarbon receptor (AhR) is a ubiquitously expressed transcription factor and its activation by environmental chemicals and by its endogenous ligand kynurenine (Kyn) has been implicated in a variety of tumour-promoting processes such as transformation, tumorigenesis and in immunosuppression that enables tumour survival and growth. Kyn is generated constitutively by human tumour cells via tryptophan (Trp)-2,3-dioxygenase (TDO), a Trp-degrading enzyme expressed in liver, brain and cancer cells. Notably, it has been shown that TDO-derived Kyn suppresses anti-tumour immune responses, thus promoting tumour-cell survival through activation of the AhR pathway. In the context of HCV infection-associated HCC, it was shown that AhR signalling is increased in HCV-infected hepatocytes, and that modifications in the expression of AhR pathway-specific genes are associated with the progression of HCV infection into HCC. Based on these observations, we present and discuss here the hypothesis that HCV infection promotes HCC by modulation of the TDO-Kyn-AhR pathway, resulting in tumorigenesis as well as in suppression of both anti-HCV and anti-tumour immune responses.

Figure 1

IDO/TDO-based HCC development and progression following persistent HCV infection. Persistent HCV infection leads to chronic inflammation, which recruits immune cells expressing IDO such as dendritic cells (DCs) and macrophages (MΦ) to the liver. This increases the levels of IDO in the liver, which along with TDO participates in the catabolism of Trp into metabolites such as Kyn, kynurenic acid and xanthurenic acid that can activate AhR signalling. Elevated levels of AhR ligands, in particular Kyn, engage with AhR on naive CD4⁺ T cells present in the liver. AhR signalling possibly coupled with signalling from cytokines such as transforming growth factor (TGF)-β leads to differentiation of naive CD4⁺ T cells to Tregs that can suppress immune responses that can prevent formation of HCC. We hypothesize that this immune suppression pathway leads to the establishment of HCC. HCC also express AhR, which following activation contributes to HCC progression. Furthermore, DC also express AhR and activation of this receptor on DC is known to increase IDO expression, which can also contribute to immune suppression using the illustrated pathway. The yellow arrows indicate up/downregulation of metabolites or a process. Furthermore, red arrows indicate catabolic enzymatic reaction of Trp, which leads to elevated AhR signalling, and the black arrows are now exclusively present to indicate the direction of the flow of the diagram.