Role of NKG2D and its ligands in cancer immunotherapy

The activating receptor natural killer group 2, member D (NKG2D) is involved in both innate and adaptive immunities, and functions as a “master switch” in determining the activation status of natural killer (NK) cells. NKG2D binds to a diverse family of ligand molecules, which are only expressed at low levels in normal cells but can be upregulated by a cellular stress response. The NKG2D-NKG2D ligand (NKG2DL) pathway has been considered to be promising target for immunotherapy because of the selective expression of “stress-induced ligands” on tumor cells and the strong NK cell activating potency of NKG2D. Diverse strategies that are aimed at targeting the NKG2D pathway for cancer therapy are based on a thorough understanding of this mechanism, as well as that of NKG2D-mediated cancer immunity. In this review, we summarize the major findings regarding the antitumor immune response mediated by the NKG2D receptor and its ligands, and discuss the potential clinical applications of targeting the NKG2D/NKG2DL pathway for immunotherapy in cancer patients.