Human NKG2D ligand regulation of Natural Killer cell function and its implications in Cancer and Inflammation

Abstract

Abstract NKG2D is an activating lymphocyte receptor which plays an essential role in stimulating immune responses against tumors. The importance of ligand-induced activation of NKG2D in controlling tumor growth has been well established in various animal models. Amongst diverse NKG2D ligands, MHC I chain related molecule MICA/B is expressed most prevalently in human cancers, but absent in rodents. Proteolytically shed-form of MICA/B (sMIC) has been shown to correlate with advanced cancer stages in patients. Previous studies in our lab using two humanized bi-transgenic mice, one expressing native ligand (TRAMP/MICB) and alternatively expressing shedding-resistant mutant (TRAMP/MICB.A2) revealed opposite roles of the two forms of MIC ligand in tumor immunity. Mice with high levels of sMIC exhibited augmented tumor progression, whereas mice expressing MICB.A2 in tumors enjoyed tumor-free survival; raising an intriguing question of why do these similar forms of MIC have different effects on tumor immunity. To address this, we investigated the signaling events and functional outcomes in NK cells upon stimulation by the two forms of ligands. Co-culture studies of NK cells with tumor cells expressing sMICB and MICB.A2 revealed elevated pro-inflammatory cytokine production by NK cells upon stimulation with sMICB. In contrast, NK cells stimulated with MICB.A2 displayed enhanced expression of cytotoxicity mediators and signaling molecules of cytotoxicity pathway. This suggests that sMICB may polarize the NKG2D signaling pathways with preferential activation of inflammatory cytokine pathways. Our data has uncovered a potential mechanism by which sMIC promotes tumor progression and endorses sMIC as a viable target for cancer immunotherapy.