Glucose metabolism controls human γδ T-cell-mediated tumor immunosurveillance in diabetes

Patients with type 2 diabetes mellitus (T2DM) have an increased risk of cancer. The effect of glucose metabolism on gamma delta T cells and their impact on tumor surveillance remain unknown. Here, we showed that high glucose induced Warburg effect type of bioenergetic profile in V gamma 9V delta 2 T cells, leading to excessive lactate accumulation, which further inhibited lytic granule secretion by impairing the trafficking of cytolytic machinery to the V gamma 9V delta 2 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 V gamma 9V delta 2 T cells. These results suggest that the impaired antitumor activity of V gamma 9V delta 2 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.

Automated summary

Patients with type 2 diabetes mellitus have an increased risk of cancer, with dysregulated glucose metabolism potentially impairing the anticancer activity of immune cells. Restoring AMPK pathway through metformin treatment may improve tumor immunosurveillance.