Glucose controls the antitumor activity of V[gamma]9V[delta]2-T cells based on AMPK activation

Abstract

Cellular metabolism controls the biological profiles, including proliferation, differentiation, and functional responses of cytotoxic lymphocytes. As a chronic metabolism syndrome, type 2 diabetes mellitus (T2DMs) characterized by abnormally elevated blood glucose levels has increased cancer incidence. As one of the primary nutrients for supporting the normal biological activities of cytotoxic lymphocytes, glucose may play a critical role in their ability of tumor surveillance. It has been well known about the effects of dysregulated metabolism, such as lipid accumulation, on the functional responses of immune cells like T cells and NK cells. However, as a promising clinic strategy in the immune cell-based immunotherapy in cancer, the biological profiles of Vγ9Vδ2-T cells in T2DMs patients, and the roles of Vγ9Vδ2- T cells in the development of T2DM-related cancers remain unknown. Vγ9Vδ2-T cells are innate-like T cells with lytic activity. Their activation is unrestricted by a major histocompatibility complex (MHC), making them excellent potential in cancer therapy. As cytotoxic lymphocytes, Vγ9Vδ2-T cells can kill tumor cells by directly secreting cytolytic molecules or indirectly regulating the cytotoxic responses of other immune cells. However, it is unknown about the impacts of dysregulated metabolism, especially hyperglycemia, on the tumor immune surveillance of Vγ9Vδ2-T cells. Here we found a "Warburg effect"-like abnormal bioenergetic profiles in Vγ9Vδ2-T cells induced by high glucose, leading to a high level of lactate accumulation. Further, high concentrations of lactate accumulation caused complete cellular metabolism "paralysis" like decreased AMPK activation in Vγ9Vδ2-T cells, which inhibited the secretion of lytic granules through the depolarization of lytic granules and MTOC at the synapse formed between Vγ9Vδ2-T cells and target tumor cells, resulting in impaired antitumor abilities of Vγ9Vδ2-T cells against different types of tumors. Interestingly, AMPK reactivation by metformin and glucose control by switching glucose concentration from high to a normal level significantly reversed all abnormal biological profiles of Vγ9Vδ2-T cells induced by high glucose both in vivo and ex vivo. Our results demonstrate that hyperglycemia impairs the cytotoxic abilities of Vγ9Vδ2-T cells, which could be restored by metformin treatment and glucose control. This study suggests that glucose metabolic reprogramming by targeting AMPK reactivation may improve tumor immune surveillance in patients with T2DMs.