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

Nature volume 513, pages 559563 (25 September 2014) | Download Citation

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Abstract

Macrophages have an important role in the maintenance of tissue homeostasis1. 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 composition2. Similarly to macrophages in normal tissues and organs, macrophages in tumours (tumour-associated macrophages) perform some key homeostatic functions that allow tumour maintenance and growth3,4,5. 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.

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Acknowledgements

We thank members of the Medzhitov laboratory for discussions, L. Xu, C. Annicelli, S. Cronin and G. Tokmoulina for animal care and technical help, and N. Palm for critical feedback on the manuscript. O.R.C. is supported by the National Cancer Institute (1K08CA172580-01), the Yale Center for Clinical Investigation (5KL2RR024138), the Yale SPORE in Skin Cancer (1 P50 CA121974), the Damon Runyon Cancer Research Foundation (DRG 108-09) and the Dermatology Foundation. R.M.’s laboratory is supported by The Blavatnik Family Foundation, grants from the National Institutes of Health (AI046688, AI089771 and CA157461) and the Howard Hughes Medical Institute.

Author information

Affiliations

  1. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA

    • Oscar R. Colegio
    • , Ngoc-Quynh Chu
    • , Alison L. Szabo
    • , Thach Chu
    • , Anne Marie Rhebergen
    • , Vikram Jairam
    • , Nika Cyrus
    • , Carolyn E. Brokowski
    • , Stephanie C. Eisenbarth
    •  & Ruslan Medzhitov
  2. Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut 06520-8059, USA

    • Oscar R. Colegio
  3. Yale-New Haven Transplantation Center, Yale University School of Medicine, New Haven, Connecticut 06519-1369, USA

    • Oscar R. Colegio
  4. Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520-8028, USA

    • Oscar R. Colegio
    •  & Ruslan Medzhitov
  5. Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8035, USA

    • Stephanie C. Eisenbarth
  6. Department of Chemistry, Yale University School of Medicine, New Haven, Connecticut 06520-8107, USA

    • Gillian M. Phillips
    •  & Andrew J. Phillips
  7. Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8020, USA

    • Gary W. Cline
  8. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA

    • Ruslan Medzhitov

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Contributions

O.R.C. and R.M. conceived the project, designed the experimental approach, interpreted data and wrote the manuscript. N.-Q.C. and A.L.S. designed and performed experiments and wrote the manuscript. T.C., A.M.R., V.J., N.C., C.E.B., G.M.P. and G.W.C. designed and performed experiments and analysed data. S.C.E. and A.J.P. designed experiments, analysed data and provided key expertise.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ruslan Medzhitov.

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DOI

https://doi.org/10.1038/nature13490

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