mTOR signaling pathway regulate glucose metabolism and function of CD4 + Tregs in SKOV3 growth environment

Abstract Ovarian cancer is the most deadly gynecological malignancy, and immunotherapy is expected to be an important strategy to improve the prognosis of patients. However, the complex immunosuppressive microenvironment is a major obstacle to the immunotherapy of ovarian cancer. Studies have shown that TLRs can regulate the differentiation and function of T cells directly or indirectly, the activation of TLR8 signal can regulate the glycometabolism pathway of CD4+ Tregs and thus regulate its function. But the pathway through which TLR8 regulates the glucose metabolism of CD4+ Tregs is still unclear. It was found that the positive expression rates of mTOR in CD4+ Tregs of OC were significantly higher than that in HC, and also significantly higher than that in CD4+ Teffs of OC. What’s more, compared with CD4+ Teffs group, CD4+ Tregs highly expressed genes and proteins related to mTOR signal. After blocking mTOR signal of CD4+ Tregs and CD4+ Teffs, the expression levels of genes and proteins related to glucose metabolism were lower than that of the control group and levels of glucose uptake and glycolysis were also declined. At the same time, inhibition of mTOR signal and activation of TLR8 signal have a coordinated inhibitory effect on the glucose metabolism and immunosuppressive function of CD4+ Tregs. Furthermore, the key molecule of TLR8 signal p38 MAPK controls mTOR signal and in the process of TLR8-mediated reversal of CD4+ Tregs inhibitory function, mTOR signal plays an important role, which suggested that activation of TLR8 signal inhibited glucose metabolism of CD4+ Tregs by down-regulating mTOR signaling and thus reversed the immunosuppressive functions of CD4+ Tregs in growth environment of ovarian cancer cells.