Low-Density Lipoprotein Uptake Inhibits The Activation And Antitumor Functions Of Human V Gamma 9v Delta 2 T Cells

V gamma 9V delta 2 T cells, the main subset of gamma delta T lymphocytes in human peripheral blood, are endowed with antitumor functions such as cytotoxicity and IFN gamma production. These functions are triggered upon T-cell receptor-dependent activation by non-peptidic prenyl pyrophosphates (phosphoantigens) that are selective agonists of V gamma 9V delta 2 T cells, and which have been evaluated in clinical studies. Because phosphoantigens have shown interindividual variation in V gamma 9V delta 2 T-cell activities, we asked whether metabolic resources, namely lipids such as cholesterol, could affect phosphoantigen-mediated V gamma 9V delta 2 T-cell activation and function. We show here that V gamma 9V delta 2 T cells express the LDL receptor upon activation and take up LDL cholesterol. Resulting changes, such as decreased mitochondrial mass and reduced ATP production, correlate with downregulation of V gamma 9V delta 2 T-cell activation and functionality. In particular, the expression of IFN gamma, NKG2D, and DNAM-1 were reduced upon LDL cholesterol treatment of phosphoantigen-expanded V gamma 9V delta 2 T cells. As a result, their capacity to target breast cancer cells was compromised both in vitro and in an in vivo xenograft mouse model. Thus, this study describes the role of LDL cholesterol as an inhibitor of the antitumor functions of phosphoantigen-activated V gamma 9V delta 2 T cells. Our observations have implications for therapeutic applications dependent on V gamma 9V delta 2 T cells. (C) 2018 AACR.