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Supporting data for “Glucose controls the antitumor activity of Vγ9Vδ2-T cells based on AMPK activation”
Immunometabolism is currently great research interest. 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)
characterised by an abnormally elevated levels of blood glucose has a high risk and increased incidence from many types of cancers. Glucose as one of the main nutrient for supporting the normal biological activities of cytotoxic lymphocytes may play critical roles in their ability of tumor surveillance. It has 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 profile of Vγ9Vδ2-T cells in T2DMs patients, and the roles of Vγ9Vδ2-T cells on the development of T2DM-related cancers still remain unknown.
Vγ9Vδ2-T cells are innate-like T cells with lytic activity, their activation is unrestricted by major histocompatibility complex (MHC), which makes them kill tumor cells quickly. Indeed, as cytotoxic lymphocytes, Vγ9Vδ2-T cells have efficient abilities against different types of tumors. They can kill tumor cells by directly secreting of 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 ability of tumor immune surveillance of Vγ9Vδ2-T cells. Here we found that high glucose caused an “Warburg effect”- liked abnormal bioenergetic profile of Vγ9Vδ2-T cells, leading to a high level of lactic acid accumulation. High concentrations of lactic acid accumulation further 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 the target tumor cells, resulting in impaired antitumor abilities of Vγ9Vδ2-T cells against different types of tumors. Interestingly, AMPK activation by metformin and glucose control by switching glucose from high to a normal level significantly reversed all of the abnormal biological profiles of Vγ9Vδ2-T cell induced by high glucose both in vivo and ex vivo. Our results demonstrated that hyperglycemia impaired 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 activation may improve tumor immunosurveillance in the patients with T2DMs.