Lactate modulation of immune responses in inflammatory versus tumour microenvironments

Abstract

The microenvironment in cancerous tissues is immunosuppressive and pro-tumorigenic, whereas the microenvironment of tissues affected by chronic inflammatory disease is pro-inflammatory and anti-resolution. Despite these opposing immunological states, the metabolic states in the tissue microenvironments of cancer and inflammatory diseases are similar: both are hypoxic, show elevated levels of lactate and other metabolic by-products and have low levels of nutrients. In this Review, we describe how the bioavailability of lactate differs in the microenvironments of tumours and inflammatory diseases compared with normal tissues, thus contributing to the establishment of specific immunological states in disease. A clear understanding of the metabolic signature of tumours and inflammatory diseases will enable therapeutic intervention aimed at resetting the bioavailability of metabolites and correcting the dysregulated immunological state, triggering beneficial cytotoxic, inflammatory responses in tumours and immunosuppressive responses in chronic inflammation.

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Fig. 1: Immunomodulatory effects of lactate in the inflammatory disease microenvironment — arthritic synovium as a paradigm.
Fig. 2: Lactate in the tumour microenvironment.

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Acknowledgements

C.M. was supported by a Medical Research Council Project Grant (MR/T016736/1), a British Heart Foundation Fellowship (FS/12/38/29640), a Fondazione Cariplo Project Grant (2015-0552) and a University of Birmingham Professorial Research Fellowship. P.-C.H. was supported, in part, by a Swiss National Science Foundation project grant (31003A_182470), a European Research Council Starting Grant (802773-MitoGuide), an EMBO Young Investigator award and a Cancer Research Institute Clinic and Laboratory Integration Program (CLIP) Investigator award. Original figures were created with BioRender.com.

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The authors contributed equally to all aspects of the article.

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Correspondence to Ping-Chih Ho or Claudio Mauro.

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P.-C.H. is scientific adviser for Elixiron Immunotherapeutics and receives research funding from Roche. P.-C.H. has received honorarium from Chungai and Pfizer. The other authors declare no competing interests.

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Nature Reviews Immunology thanks L. O’Neill and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Pentose phosphate pathway

A metabolic pathway that is parallel to glycolysis and that generates NADPH, a substrate used for lipogenesis and glutathione regeneration, and ribose 5-phosphate, a precursor for nucleotide synthesis in proliferating cells.

Warburg effect

A phenomenon observed in rapidly dividing cells or when robust transient responses are needed that is characterized by the conversion of glucose into lactate, even in the presence of normal levels of oxygen.

Experimental autoimmune encephalomyelitis

(EAE). A demyelinating disease of the central nervous system used as a common animal model for multiple sclerosis.

Tumour-associated macrophages

Immune cells that induce an immunosuppressive tumour microenvironment through the release of growth factors, proteolytic enzymes and inhibitory immune checkpoint proteins.

Myeloid-derived suppressor cells

A group of phenotypically heterogeneous myeloid cells that contribute to tumour expansion and chronic inflammation progression by inducing immunosuppressive mechanisms, angiogenesis and drug resistance.

Mitochondrial antiviral signalling protein

(MAVS). A mitochondrial adaptor protein activation of which induces the release of cytokines and triggers an immune response.

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Certo, M., Tsai, C., Pucino, V. et al. Lactate modulation of immune responses in inflammatory versus tumour microenvironments. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-020-0406-2

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