CCL20 Promotes The Formation Of Hepatic Ectopic Lymphoid-like Structures

Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. A ubiquitous risk factor for the development of HCC is chronic liver inflammation (hepatitis). Formation of hepatic ectopic lymphoid-like structures (ELSs) is a prominent pathological hallmark of chronic viral hepatitis, which is known to persistently activate IKK-NF-kB signaling. It was shown in our lab that in IKKβ(EE)^Hep mice, which express constitutively active IKKβ(EE) in hepatocytes, chronic IKK-NF-kB activation leads to formation of hepatic ELSs, which then promote appearance and growth of HCC. Similarly, an association between NF-kB activation and ELS formation in chronically inflamed human livers was found. Yet, our mouse model reveals that NF-kB activation is not sufficient for ELS induction, which requires additional signals.

There is an increasing interest in the CCL20-CCR6 axis in HCC, as it is highly expressed in a variety of human cancers, including HCC. CCL20 is the only chemokine known to interact with CC chemokine receptor 6 (CCR6). The ligand-receptor pair CCL20-CCR6 is responsible for the chemo-attraction of immature dendritic cells (DC) effector/memory T cells, regulatory T cells and B cells.

This study aims to assess the role of CCL20 signaling in ELS formation.

Materials and Methods: First, using immunohistochemical analysis, we identified that CCL20 is expressed in all HCC progenitor lesions in IKKβ(EE)^Hep mice. In order to assess a causative role of the CCL20-CCR6 axis in ELS and HCC induced by chronic low grade NF-ĸB activation, we used two approaches: (1) Disruption of CCL20 signaling by crossing IKKβ(EE)^Hep mice with CCR6 KO mice; (2) Overexpression of CCL20 specifically in the hepatocytes of IKKβ(EE)^Hep mice.

Results and Discussion: The disruption of CCL20 signaling in IKKβ(EE)^Hep mice resulted in reduced liver infiltration by lymphocytes, attenuated ELS neogenesis and reduced HCC tumorigenesis. CCL20 overexpression specifically in the hepatocytes of IKKβ(EE)^Hep mice accelerated the formation of ELSs.

Conclusion: Our results suggest a central role for the CCL20-CCR6 axis in ELS formation, as CCR6 depletion significantly attenuates ELS neogenesis and HCC load in IKKβ(EE)^Hep mice. Further studies are planned to define the mechanisms and immune cell types through which CCL20-CCR6 induce formation of ELSs and HCC.