Lactic Acidosis Together with GM-CSF and M-CSF Induces Human Macrophages toward an Inflammatory Protumor Phenotype
- 1 March 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Immunology Research
- Vol. 8 (3), 383-395
- https://doi.org/10.1158/2326-6066.CIR-18-0749
Abstract
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-1 alpha stabilization. The expression of some lactate-induced genes is dependent on autocrine M-CSF consumption. Finally, TAMs with protumor and inflammatory characteristics (VEGF(high) CXCL8(+) IL1 beta(+)) 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.Other Versions
Funding Information
- Ministry of Health and the Institute for Health and Medical Research (INCa-DGOS-Inserm_12558)
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