Lactic acidosis together with GM-CSF and M-CSF induces human macrophages toward an inflammatory pro-tumor phenotype

Abstract : In established tumors, tumor-associated macrophages (TAMs) orchestrate non-resolving cancer-related inflammation and produce mediators favoring tumor growth, metastasis and angiogenesis. However, the factors conferring inflammatory and pro-tumor properties on human macrophages remain largely unknown. Most solid tumors have high lactate content. We therefore analyzed the impact of lactate on human monocyte differentiation. We report that prolonged lactic acidosis induces the differentiation of monocytes into macrophages with a phenotype including pro-tumor and inflammatory characteristics. These cells produce tumor growth factors, inflammatory cytokines and chemokines as well as low amounts of IL10. These effects of lactate require its metabolism and are associated with HIF-1α stabilization. The expression of some lactate-induced genes is dependent on autocrine M-CSF consumption. Finally, TAMs with pro-tumor and inflammatory characteristics (VEGFhigh CXCL8+ IL1β+) are found in solid ovarian tumors. These results show that tumor-derived lactate links the pro-tumor features of TAMs with their inflammatory properties. Treatments that reduce tumor glycolysis or tumor-associated acidosis may help combat cancer.