NKG2D-Based Cancer Immunotherapy

Abstract

NKG2D (nature killer group 2, member D) is a C-type lectin-like activating receptor expressed by all human nature killer (NK) cells, most NKT cells, subsets of γδ T cells, and CD8 T cells. In mouse, NKG2D is also expressed by all NK cells and subsets od splenic γδ T cells and NKT cells, but only expressed by activated mouse CD8 T cells and activated mouse macrophages. NKG2D is located on a syntanic region of human choromosome 12 and on mouse chromosome 6, clustered with other NKG2 family members (Glienke et al., 1998; Ho et al., 1998) (Figure 1). NKG2D serves as an invariant immune activating receptor upon engagement by ligands expressed on target cells, transformed or viral infected cells. Engagement of NKG2D by its ligands can activate NK cell and co-stimulate CD8 and γδ T cells (Bauer et al., 1999; Groh et al., 2001; Wu et al., 2002). The activation signals transmitted by NKG2D can override inhibitory signals transmitted by other NK receptors. NKG2D is therefore referred as the master activating receptor for NK cells to sense cells under abnormal physiological stress. The ligands for NKG2D are not commonly present in normal tissues but can be induced under abnormal physiological condition, such as cellular transformation or viral infection. The expression pattern of NKG2D ligands in tumor cells has been extensively studied. Emerging experimental evidence have indicated that NKG2Dmediated immunity can be very effective for tumor clerance by activating NK cells, and in some cases CD8 T cells. However, it is widely accepted that NKG2D function is subverted in cancer patients, due to mechanisms of tumor immunoediting and immune suppressive effect of tumor microenvironment (Figure 2). Thus, inventions are in need to overcome tumor immune evasion of NKG2D immunity as an effective cancer treatment. In this chapter, we will review the basic understandings of NKG2D function in anti-tumor immunity and the challenges and advances in NKG2D-based cancer treatment.