Low-Density Lipoprotein Uptake Inhibits the Activation and Antitumor Functions of Human V{gamma}9V{delta}2 T Cells

V9V2 T cells, the main subset of T lymphocytes in human peripheral blood, are endowed with antitumor functions such as cytotoxicity and IFN production. These functions are triggered upon T-cell receptor–dependent activation by non-peptidic prenyl pyrophosphates ("phosphoantigens") that are selective agonists of V9V2 T cells, and which have been evaluated in clinical studies. Because phosphoantigens have shown interindividual variation in V9V2 T-cell activities, we asked whether metabolic resources, namely lipids such as cholesterol, could affect phosphoantigen-mediated V9V2 T-cell activation and function. We show here that V9V2 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 V9V2 T-cell activation and functionality. In particular, the expression of IFN, NKG2D, and DNAM-1 were reduced upon LDL cholesterol treatment of phosphoantigen-expanded V9V2 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 V9V2 T cells. Our observations have implications for therapeutic applications dependent on V9V2 T cells. Cancer Immunol Res; 6(4); 448–57. ©2018 AACR.

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