Introduction: NKG2D (natural killer group 2, member D) is expressed on the surface of all mouse and human NK cells, and subpopulation of T cells. Stimulation of NK cells through NKG2D triggers cell-mediated cytotoxicity and induces the production of cytokines. NKG2D binds to family of unique ligands with structurally similar to MHC class I, however, NKG2D ligands can be up-regulated in their expression on stressed cells including tumor cells unlike conventional MHC class I molecules. Mounting evidences clearly implicate that NKG2D recognition plays an important role in tumor immune surveillance.
Areas covered: While NKG2D detect for potentially dangerous cells, various inhibitory and/or escape mechanisms counteract immune surveillance system and thereby limit effective elimination of transformed tumor cells. In addition, tumors often generate an immunosuppressive microenvironment where inhibitory molecules or cytokines negatively effect the function of anti-tumor immune responses. NKG2D ligand expression can be up-regulated by transcriptional or posttranscriptional mechanisms, therefore, certain therapy targeting those regulatory mechanisms could regain the expression of NKG2D ligands on tumor cells to be detected by the host immune responses.
Expert opinion: Our knowledge in the precise mechanism of anti-tumor immunity is rapidly increasing. While NKG2D is known as primary cytotoxicity receptor in NK cell activation by recognizing 'induced-self' ligands on stressed cells including tumor cells, there are increasing evidences that NKG2D recognition can result in both immune activation and immune silencing. Future combined application of conventional cancer therapy and new therapy utilizing such stress-induced recognition systems will provide a novel opportunity to control malignant tumor progression of cancer disease.