Université d'Angers, CHU d'Angers, Inserm U1232, CRCINA, Angers, France.
Laboratoire d'Immunologie et Allergologie, CHU d'Angers, Angers, France.
Cancer Immunol Res. 2020 Mar;8(3):383-395. doi: 10.1158/2326-6066.CIR-18-0749. Epub 2020 Jan 10.
In established tumors, tumor-associated macrophages (TAM) orchestrate nonresolving cancer-related inflammation and produce mediators favoring tumor growth, metastasis, and angiogenesis. However, the factors conferring inflammatory and protumor 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 protumor 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 hypoxia-inducible factor-1α stabilization. The expression of some lactate-induced genes is dependent on autocrine M-CSF consumption. Finally, TAMs with protumor and inflammatory characteristics (VEGF CXCL8 IL1β) are found in solid ovarian tumors. These results show that tumor-derived lactate links the protumor features of TAMs with their inflammatory properties. Treatments that reduce tumor glycolysis or tumor-associated acidosis may help combat cancer.
在已建立的肿瘤中，肿瘤相关巨噬细胞（TAM）协调非解决性癌症相关炎症，并产生有利于肿瘤生长、转移和血管生成的介质。然而，赋予人类巨噬细胞炎症和促进肿瘤特性的因素在很大程度上仍然未知。大多数实体瘤具有高乳酸含量。因此，我们分析了乳酸对人单核细胞分化的影响。我们报告说，长期乳酸酸中毒诱导单核细胞分化为具有表型的巨噬细胞，包括促肿瘤和炎症特征。这些细胞产生肿瘤生长因子、炎症细胞因子和趋化因子以及少量的 IL10。乳酸的这些作用需要其代谢，并与缺氧诱导因子-1α稳定相关。一些乳酸诱导基因的表达依赖于自分泌 M-CSF 的消耗。最后，在实体卵巢肿瘤中发现了具有促肿瘤和炎症特征（VEGF CXCL8 IL1β）的 TAMs。这些结果表明，肿瘤衍生的乳酸将 TAMs 的促肿瘤特征与其炎症特性联系起来。减少肿瘤糖酵解或肿瘤相关酸中毒的治疗方法可能有助于对抗癌症。
