160P - Glucose and NKG2D Ligand Expression: A Link Between Cellular Immunogenicity and Warburg Metabolism

Abstract

ABSTRACT Natural killer group 2D (NKG2D) is an activating receptor constitutively expressed on the surface of human natural killer cells and CD8+ T-lymphocytes. The ligands for NKG2D, including MICA, are up-regulated in several pathophysiological settings, including cancer, and viral infection. In these contexts, glucose metabolism is often perturbed (the Warburg effect) and glucose levels can be low in the tumour microenvironment. We hypothesized that low glucose availability would reduce cell surface NKG2D ligand expression and lower the immunogenicity of malignant cells. Cell lines cultured in different glucose concentrations displayed a direct correlation between glucose level and cell surface expression of MICA, a key activating ligand of NKG2D. Real-time RT-PCR demonstrated an increase in MICA mRNA transcript levels with increasing glucose concentration. Chromium-release cytotoxicity assays demonstrated an NKG2D-dependent change in NK cell-mediated killing of target cells, in response to changing glucose availability. This suggests that extracellular glucose concentration may alter the susceptibility of malignant cells to immune-mediated clearance. We demonstrate that the contribution of glucose to nucleotide synthesis is necessary for the observed increase in MICA expression. In a primary cell-viral infection model of NKG2D ligand induction, we demonstrate that glucose availability determines the level of NKG2D ligand expression in the transition from healthy to infected cells. As with cell line models, reduced glucose availability in this primary cell model limits the up-regulation of NKG2D ligands observed in virus-infected cells. These results suggest that Warburg metabolism is important to support NKG2D ligand expression in these models. The reduction in NKG2D ligand expression in a low glucose environment may represent a novel immune-evasion mechanism in aberrantly vascularized tumour microenvironments. Further understanding of the downstream signaling pathways could lead to the development of novel therapeutic agents. Disclosure All authors have declared no conflicts of interest.