The synergistic effect of vitamin C and IL-15 on the anti-tumor activities of human V[gamma]9V[delta]2-T cells

Abstract

Vitamin C is the essentially water-soluble micronutrient that exerts a potent antioxidative function against oxidative damage. It also plays a critical role in energy metabolism and gene transcription. Recently, studies have showed that vitamin C can regulate innate and adaptive immunity during tumor development. Vγ9Vδ2 T-cell, as an important component of innate immune cells, is indispensable for immunosurveillance against tumors. Human Vγ9Vδ2 T-cells exhibit potent cytolytic activities against tumor cells without MHC restriction. However, the role of vitamin C in modulating immunological functions of Vγ9Vδ2 T-cells in tumor immunity remains unclear. Herein, we reported that Vitamin C or IL-15 or Vitamin C plus IL-15 could increase the cell number and promote the proliferation of human Vγ9Vδ2 T-cells in vitro. Human Vγ9Vδ2 T-cells expanded by Vitamin C or IL-15 or Vitamin C plus IL-15 could exert more potent cytotoxic ability against A549 tumor cells. In the tumor-bearing immunodeficiency mice, Vitamin C plus IL-15 treatment could sustain the proliferative activity of Vγ9Vδ2 T-cells against the tumor induced-immunosuppressive microenvironment. Vitamin C and IL-15 synergistically down-regulated PD-1+ expression and sustained CD107a+ expression on Vγ9Vδ2 T-cells cells in vivo. In humanized mice inoculated with A549 tumor cells, adoptive transfer of Vγ9Vδ2 T-cells expanded by vitamin C and IL-15 significantly inhibited tumor growth and prolonged the survival of humanized mice. Taken together, our study demonstrated that vitamin C has a synergistic effect with IL-15 on enhancing the proliferation and cytotoxic activity of PAM-expanded Vγ9Vδ2 T-cells in vitro and inhibiting tumor growth and prolonging the survival in humanized mice.