Role of the activating NK cell receptor NKG2D in models of liver inflammation and tumorigenesis

Inflammation is a fundamental protective immune response that is now accepted as one of the hallmarks of cancer as it can provide pro-tumorigenic signals and subvert immunosurveillance. The activating receptor NKG2D, expressed on both innate and adaptive immune cells, binds to several ligands expressed by target cells and it is known to be critical in the surveillance of ligand-expressing spontaneous tumours. NKG2D has recently emerged as an important player in inflammatory disorders but its precise relevance in inflammation-driven cancer remains elusive. In this study, the role played by NKG2D in a chemically induced model of hepatocellular carcinoma (HCC) is addressed by using NKG2D-deficient mice to provide evidence of a novel and unexpected role for NKG2D as a tumour promoter. The study shows that the presence of NKG2D in this model accelerates tumour growth, favours the recruitment of CD8+T cells to the inflamed liver tissue and exacerbates the pro-inflammatory milieu. NKG2D contributes to liver damage that drives chronic cycles of hepatocyte death and proliferation favouring tumour progression. The NKG2D/NKG2D ligand pathway provides an additional mechanism linking chronic inflammation to tumour development in the context of HCC exposing the need to selectively target the types of cancer that will benefit from NKG2D-based immunotherapy. In contrast with the HCC model, a NKG2D effect is not observed at early stages of liver inflammation in a short-term model of acute inflammation and liver damage. Mechanisms that regulate the recruitment and location of immune cells at sites of inflammation are poorly understood and no data are available regarding the importance of activating receptors in this mobilization process. For this reason a protocol for real time imaging of natural killer (NK) cells in the liver tissue using intravital confocal or two-photon laser-scanning microscopy (TPSLM) was established to address NK cell dynamics in vivo in the liver.Open Acces