The Role and Regulation of the NKG2D/NKG2D Ligand System in Cancer

SIMPLE SUMMARY: The immune system provides surveillance measures to identify and remove damaged cell types at an early stage. One important example involves the NKG2D receptor, which is expressed on a range of white blood cells. In humans, NKG2D binds to a family of eight proteins known as NKG2D ligands. NKG2D ligands are generally absent from the surfaces of healthy cells. By contrast, they are induced by various forms of cell stress, most notably DNA damage, which is very common in cancer cells. By this means, NKG2D provides a rapid response system to detect and eradicate potentially dangerous cells. Expression of NKG2D ligands on cancer cells can be boosted or reduced using a range of drugs, providing opportunities for therapeutic intervention. However, the NKG2D/NKG2D ligand system is double-edged since it can also fuel chronic inflammation which, in turn, can increase cancer development and progression. ABSTRACT: The family of human NKG2D ligands (NKG2DL) consists of eight stress-induced molecules. Over 80% of human cancers express these ligands on the surface of tumour cells and/or associated stromal elements. In mice, NKG2D deficiency increases susceptibility to some types of cancer, implicating this system in immune surveillance for malignancy. However, NKG2DL can also be shed, released via exosomes and trapped intracellularly, leading to immunosuppressive effects. Moreover, NKG2D can enhance chronic inflammatory processes which themselves can increase cancer risk and progression. Indeed, tumours commonly deploy a range of countermeasures that can neutralise or even corrupt this surveillance system, tipping the balance away from immune control towards tumour progression. Consequently, the prognostic impact of NKG2DL expression in human cancer is variable. In this review, we consider the underlying biology and regulation of the NKG2D/NKG2DL system and its expression and role in a range of cancer types. We also consider the opportunities for pharmacological modulation of NKG2DL expression while cautioning that such interventions need to be carefully calibrated according to the biology of the specific cancer type.