CCL20 in liver inflammation and carcinogenesis

Primary liver cancer mainly comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). It is estimated that approximately 20% of all cancers develop in the background of chronic inflammation. Tertiary lymphoid structures (TLSs) are key effectors of adaptive immunity. We utilize IKKβ(EE)^Hep mice which express constitutively active IKKβ(EE) in hepatocytes, resulting in appearance of TLSs highly similar to inflammatory aggregates observed in hepatitis C infected human livers. In contrast to the well-established tumor protective role of TLSs, hepatic TLSs in IKKβ(EE)^Hep mice promote liver tumorigenesis. Here we address the role of the CC-chemokine ligand 20 (CCL20), which is highly expressed by tumor progenitors, in TLS function.

CCL20 is the only chemokine known to interact with the CC-chemokine receptor 6 (CCR6), and can be abundantly expressed in the liver. High levels of CCL20 are correlated with poor prognosis in HCC patients. Our analysis of open-access data-bases revealed that CCL20 expression is elevated in both human HCC and iCCA tumors compared to non-tumor parenchyma. The disruption of CCL20 signaling in IKKβ(EE)^Hep mice resulted in marked reduction of hepatic TLS formation, subsequently leading to a dramatic decrease in iCCA tumor load, but not in HCC, revealing a specific role of the CCL20-CCR6 axis in iCCA development. These findings were supported by the results of CCL20 overexpression in hepatocytes of IKKβ(EE)^Hep mice, which resulted in selective promotion of iCCA but not HCC tumorigenesis.

This study identifies CCL20 as a specific tumor progenitor-derived factor that alters TLS function towards tumor promotion in liver cancer.