Professor University of Hong Kong Hong Kong, Hong Kong
Abstract Text: Patients with type 2 diabetes mellitus (T2DM) have a high risk of cancer. The effect of glucose metabolism on γδ-T cells and their impact on tumor surveillance remain unknown. Here, we show that high glucose induces a “Warburg effect”-like bioenergetic profile in Vγ9Vδ2-T cells, leading to excessive lactate accumulation, which further inhibits lytic granule secretion by preventing the trafficking of cytolytic machinery to the Vγ9Vδ2-T cell-tumor synapse through suppressing AMPK activation, and finally resulting in loss of their antitumor activity in vitro, in vivo and in patients. Strikingly, activating AMPK pathway by glucose control or metformin treatment reverses the metabolic abnormalities and restores the antitumor activity of Vγ9Vδ2-T cells. These results suggest that the impaired antitumor activity of Vγ9Vδ2-T cells induced by dysregulated glucose metabolism may contribute to the increased cancer risk in T2DM patients, and that metabolic reprogramming through targeting AMPK pathway by using metformin may improve their tumor immunosurveillance.
