Lactate-Modulated the Immunosuppressive Function of Myeloid-Derived Suppressor Cells through TET2-mediated SGK1 demethylation

Myeloid-derived suppressor cells (MDSCs) is a collection of myeloid-derived heterogenetic cells, which has immunosuppressive capabilities in the occurrence and development of tumor. We found that compared with spleen-derived MDSCs (SP-MDSCs) of lung cancer mice xenograft model, tumor -derived MDSCs (T-MDSCs) had stronger immunosuppressive function which was caused by lactate in the tumor microenvironment. Here we revealed that lactate was involved in regulating the function and glycolysis of MDSCsand serum and glucocorticoid-inducible kinase 1(SGK1) should be an important factor during this process. Further studies demonstrated that lactate could down-regulate the DNA methylation level of SGK1 by regulating the Ten-Eleven-Translocation-2 (TET2). In summary, our findings indicated an indispensable role of lactate in the immunosuppressive functions and glycolysis of MDSCs for the first time and offer an effective therapeutic target for anti-tumor therapy.