Expression of NKG2D ligands is downregulated by beta-catenin signaling and associates with HCC aggressiveness

Abstract Background /Aims: The NKG2D system is a potent immunosurveillance mechanism in cancer based on recognition of the NKG2D ligands expressed on tumour cells by activating receptor natural killer group 2, member D (NKG2D) on immune cells. Here, we evaluated the expression of NKG2D ligands in HCC, in both humans and mice, taking the genomic features of HCC tumours into account. Methods The expression of NKG2D ligands (MICA, MICB, ULBP1 and ULBP2) was analysed in large human HCC datasets by Fluidigm TaqMan and RNAseq methods, and in two mouse models (mRNA and protein levels) reproducing the features of both major groups of human tumours. Results We provide compelling evidence that expression of the MICA and MICB ligands in human HCC is associated with tumour aggressiveness and poor patient outcome. We also found that the expression of ULBP1 and ULBP2 was associated with poor patient outcome, and was downregulated in CTNNB1-mutated HCCs displaying low levels of inflammation and associated with a better prognosis. We also found an inverse correlation between ULBP1/2 expression levels and the expression of β-catenin target genes in HCC patients, suggesting a role for β-catenin signalling in inhibiting expression. We showed in HCC mouse models that β-catenin signalling downregulated the expression of Rae-1 NKG2D ligands, orthologs of ULBPs, through TCF4 binding. Conclusions We demonstrate that the expression of NKG2D ligands is associated with aggressive liver tumorigenesis and that the downregulation of these ligands by β-catenin signalling may account for the less aggressive phenotype of CTNNB1-mutated HCC tumours. Lay summary The NKG2D system is a potent immunosurveillance mechanism in cancer. The expression of NKG2D ligands has been little investigated in HCC. We show here, in a large cohort of HCC patients and dedicated HCC mouse model, that the expression of NKG2D ligands is associated with aggressive tumorigenesis and downregulated in CTNNB1-mutated HCC. We also show that β-catenin signalling downregulates NKG2D ligands in mice.