Low-Density Lipoprotein Uptake Inhibits the Activation and Antitumor Functions of Human Vg9Vd2 T Cells

Vg9Vd2 T cells, the main subset of gd T lymphocytes in human peripheral blood, are endowed with antitumor functions such as cytotoxicity and IFNg production. These functions are triggered upon T-cell receptor–dependent activation by non-peptidic prenyl pyrophosphates ("phosphoantigens") that are selective agonists of Vg9Vd2 T cells, and which have been evaluated in clinical studies. Because phosphoantigens have shown interindividual variation in Vg9Vd2 T-cell activities, we asked whether metabolic resources, namely lipids such as cholesterol, could affect phosphoantigen-mediated Vg9Vd2 T-cell activation and function. We show here that Vg9Vd2 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 Vg9Vd2 T-cell activation and functionality. In particular, the expression of IFNg , NKG2D, and DNAM-1 were reduced upon LDL cholesterol treatment of phosphoantigen-expanded Vg9Vd2 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 Vg9Vd2 T cells. Our observations have implications for therapeutic applications dependent on Vg9Vd2 T cells. Cancer Immunol Res; 6(4); 448–57. 2018 AACR.