The immunoreceptor NKG2D belongs to the best-characterized activating receptors of cytotoxic lymphocytes. NKG2D binds to a variety of cell surface glycoproteins distantly related to MHC class I molecules, termed NKG2D ligands (NKG2DL). NKG2DL are inducibly expressed upon cellular stress, viral infection or malignant transformation thus marking 'stressed' or 'harmful' cells for clearance through NKG2D+ lymphocytes. However, certain viruses and many tumors employ various strategies to escape from NKG2D-mediated immunosurveillance. Areas covered: Expression and regulation of both NKG2D and NKG2DL, especially at sites of immune responses or in the tumor microenvironment, as well as mechanisms of NKG2D escape strategies, as their understanding is key for harnessing the NKG2D/NKG2DL axis for immunotherapy. Studies documenting the importance of the NKG2D/NKG2DL axis for cancer immunosurveillance. Therapeutic approaches targeting the NKG2D/NKG2DL axis in cancer. Expert opinion: The selective expression of NKG2DL on malignant cells together with the strong activating potency of NKG2D renders the NKG2D/NKG2DL axis a prime target for immunotherapies. Based on a thorough understanding of the NKG2D/NKG2DL system as well as of the most relevant escape strategies of tumors, the diligent and thoughtful design of novel treatment modalities harnessing the NKG2D/NKG2DL axis holds great promise for the future therapy of cancer.
Keywords: MICA; NKG2D; ULBP; cytotoxic lymphocytes; immunotherapy.