Abstract 3802: Human NKG2D ligand regulation of Natural Killer cell function and its implications in cancer and inflammation

Abstract

Abstract The significance of ligand-induced activation of Natural Killer cell activating receptor NKG2D in controlling tumor growth has been well established in various experimental animal models. Amongst different types of NKG2D ligands, MHC I chain related molecule MICA/B is expressed most prevalently in various human malignancies, but has not been found in rodent family. Proteolytic-mediated shed-form of soluble MICA/B (sMIC) has been shown to suppress the immune system and correlate with advanced disease stages in cancer patients. Previous studies in our lab using two humanized bi-transgenic mice, one expressing native ligand (TRAMP/MICB) and alternatively expressing the shedding-resistant mutant (TRAMP/MICB.A2) revealed opposite roles of membrane-bound and soluble form of MIC in regulating tumor immunity. Mice with high levels of sMIC exhibited increased tumor progression, whereas mice expressing membrane-bound MICB.A2 in tumors enjoyed tumor-free survival. These findings raised the intriguing question of why do these structurally similar forms of MIC have vastly different effects on tumor immunity. To address this question, we investigated the signaling events and functional outcomes in NK cells upon stimulation by the two forms of ligands. In vitro co-culture studies of NK cells with tumor cell lines 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 signaling through sMICB may polarize the NKG2D signaling pathways with preferential activation of inflammatory cytokine pathways. Our data has uncovered a new potential mechanism whereby sMIC promotes tumor progression and supports the notion that sMIC is a viable target for cancer immunotherapy. Citation Format: Payal Dhar, Jennifer Wu. Human NKG2D ligand regulation of Natural Killer cell function and its implications in cancer and inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3802.