Patients with type 2 diabetes mellitus(T2DM)have an increased risk of cancer.The effect of glucose metabolism onγδT cells and their impact on tumor surveillance remain unknown.Here,we showed that high glucose induce...Patients with type 2 diabetes mellitus(T2DM)have an increased risk of cancer.The effect of glucose metabolism onγδT cells and their impact on tumor surveillance remain unknown.Here,we showed that high glucose induced Warburg effect type of bioenergetic profle in Vy9vδ2 T cells,leading to excessive lactate accumulation,which further inhibited lytic granule secretion by impairing the traffcking of cytolytic machinery to the Vy9vδ2 T-cell-tumor synapse by suppressing AMPK activation and resulted in the loss of antitumor activity in vitro,in vivo and in patients.Strikingly,activating the AMPK pathway through glucose control or metformin treatment reversed the metabolic abnormalities and restored the antitumor activity of Vy9vδ2 T cells.These results suggest that the impaired antitumor activity of Vy9vδ2 T cells induced by dysregulated glucose metabolism may contribute to the increased cancer risk in T2DM patients and that metabolic reprogramming by targeting the AMPK pathway with metformin may improve tumor immunosurveillance.展开更多
基金Seed Funding for Strategic Interdisciplinary Research Scheme,University of Hong Kong,and the General Research Fund,Research Grants Council of Hong Kong(17122222,17122519,17126317),Hong Kong SAR,ChinaThis work was also partly supported by the National Natural Science Foundation of China(32000616),China.
文摘Patients with type 2 diabetes mellitus(T2DM)have an increased risk of cancer.The effect of glucose metabolism onγδT cells and their impact on tumor surveillance remain unknown.Here,we showed that high glucose induced Warburg effect type of bioenergetic profle in Vy9vδ2 T cells,leading to excessive lactate accumulation,which further inhibited lytic granule secretion by impairing the traffcking of cytolytic machinery to the Vy9vδ2 T-cell-tumor synapse by suppressing AMPK activation and resulted in the loss of antitumor activity in vitro,in vivo and in patients.Strikingly,activating the AMPK pathway through glucose control or metformin treatment reversed the metabolic abnormalities and restored the antitumor activity of Vy9vδ2 T cells.These results suggest that the impaired antitumor activity of Vy9vδ2 T cells induced by dysregulated glucose metabolism may contribute to the increased cancer risk in T2DM patients and that metabolic reprogramming by targeting the AMPK pathway with metformin may improve tumor immunosurveillance.
