Metformin blocks myeloid-derived suppressor cell accumulation through AMPK-DACH1-CXCL1 axis.

Purpose : Tumor development has been closely linked to tumor microenvironment, particularly in terms of myeloid-derived suppressive cells (MDSCs), a heterogeneous population of immature myeloid cells that protect tumors from elimination by immune cells. Approaches aimed at blocking MDSC accumulation could improve cancer clinical outcome. Experimental Design : We investigated that metformin suppressed MDSC migration to inhibit cancer progression. Primary tumor tissues were incubated with metformin, and proinflammatory chemokine production was measured. To study MDSC chemotaxis in vivo , BALB/C nude mice were injected subcutaneously with TE7 cells and treated with metformin. Migration of adoptively transferred MDSCs was analyzed using flow cytometry and immunohistochemistry. Results : The frequency of tumor-infiltrated polymorphonuclear (PMN)-MDSCs was increased compared to their circulating counterparts. There was a significant correlation between PMN-MDSCs accumulation in tumors and ESCC prognosis. Moreover, PMN-MDSCs displayed immunosuppressive activity in vitro . Treatment with metformin reduced MDSC migration in patients. Metformin inhibited CXCL1 secretion in ESCC cells and tumor xenografts by enhancing AMPK phosphorylation and inducing DACH1 expression, leading to NF-κB inhibition and reducing MDSC migration. Knockdown of AMPK and DACH1 expression blocked the effect of metformin on MDSC chemotaxis. Conclusions : A novel anti-tumor effect of metformin, which is mediated by reducing PMN-MDSC accumulation in the tumor microenvironment via AMPK/DACH1/CXCL1 axis.