Functional polarization of tumour-associated macrophages by tumour-derived lactic acid

• Published in: Nature (London) 2014-09, Vol.513 (7519), p.559-563
• Main Authors: Colegio, Oscar R., Chu, Ngoc-Quynh, Szabo, Alison L., Chu, Thach, Rhebergen, Anne Marie, Jairam, Vikram, Cyrus, Nika, Brokowski, Carolyn E., Eisenbarth, Stephanie C., Phillips, Gillian M., Cline, Gary W., Phillips, Andrew J., Medzhitov, Ruslan
• Format: Article
• Language: English
• Subjects: 13/106; 13/31; 13/95; 631/80/86; Acids; Animals; Arginase - genetics; Arginase - metabolism; Cancer; Carcinoma, Lewis Lung - pathology; Cell Communication - drug effects; Cell Division - drug effects; Cell growth; Culture Media, Conditioned - chemistry; Culture Media, Conditioned - pharmacology; Development and progression; Female; Genetic aspects; Glycolysis; Homeostasis; Humanities and Social Sciences; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Kinases; Lactic acid; Lactic Acid - metabolism; Lactic Acid - pharmacology; letter; Macrophages; Macrophages - metabolism; Macrophages - pathology; Male; Melanoma, Experimental - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; multidisciplinary; Neoplasms - metabolism; Neoplasms - pathology; Physiological aspects; RNA, Messenger - analysis; RNA, Messenger - genetics; Science; Solubility; Tissues; Tumors; Up-Regulation - drug effects; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13490

The growth of tumours is supported by tumour production of lactic acid, which polarizes tumour-associated macrophages to an M2 phenotype through a pathway dependent on hypoxia-inducible factor 1α. The making of tumour-associated macrophages Tumour-associated macrophages (TAMs) are thought to promote tumorigenesis through a variety of mechanisms, but the communication signals between tumours and macrophages are poorly defined. This study shows that tumour-derived lactic acid induces the expression of vascular endothelial growth factor (VEGF) and phenotypic polarization to an alternatively activated or M2 macrophage-like state in TAMs. The action of lactic acid is mediated by hypoxia-inducible factor 1α and is associated with arginase 1 expression and tumour growth. These findings identify a means of communication between macrophages and tumour cells that is most probably a variant of a system evolved to promote homeostasis in normal tissues. Macrophages have an important role in the maintenance of tissue homeostasis 1 . To perform this function, macrophages must have the capacity to monitor the functional states of their ‘client cells’: namely, the parenchymal cells in the various tissues in which macrophages reside. Tumours exhibit many features of abnormally developed organs, including tissue architecture and cellular composition 2 . Similarly to macrophages in normal tissues and organs, macrophages in tumours (tumour-associated macrophages) perform some key homeostatic functions that allow tumour maintenance and growth 3 , 4 , 5 . However, the signals involved in communication between tumours and macrophages are poorly defined. Here we show that lactic acid produced by tumour cells, as a by-product of aerobic or anaerobic glycolysis, has a critical function in signalling, through inducing the expression of vascular endothelial growth factor and the M2-like polarization of tumour-associated macrophages. Furthermore, we demonstrate that this effect of lactic acid is mediated by hypoxia-inducible factor 1α (HIF1α). Finally, we show that the lactate-induced expression of arginase 1 by macrophages has an important role in tumour growth. Collectively, these findings identify a mechanism of communication between macrophages and their client cells, including tumour cells. This communication most probably evolved to promote homeostasis in normal tissues but can also be engaged in tumours to promote their growth.