Review Article | Published:

Immune control by amino acid catabolism during tumorigenesis and therapy

Nature Reviews Cancer (2019) | Download Citation

Abstract

Immune checkpoints arise from physiological changes during tumorigenesis that reprogramme inflammatory, immunological and metabolic processes in malignant lesions and local lymphoid tissues, which constitute the immunological tumour microenvironment (TME). Improving clinical responses to immune checkpoint blockade will require deeper understanding of factors that impact local immune balance in the TME. Elevated catabolism of the amino acids tryptophan (Trp) and arginine (Arg) is a common TME hallmark at clinical presentation of cancer. Cells catabolizing Trp and Arg suppress effector T cells and stabilize regulatory T cells to suppress immunity in chronic inflammatory diseases of clinical importance, including cancers. Processes that induce Trp and Arg catabolism in the TME remain incompletely defined. Indoleamine 2,3 dioxygenase (IDO) and arginase 1 (ARG1), which catabolize Trp and Arg, respectively, respond to inflammatory cues including interferons and transforming growth factor-β (TGFβ) cytokines. Dying cells generate inflammatory signals including DNA, which is sensed to stimulate the production of type I interferons via the stimulator of interferon genes (STING) adaptor. Thus, dying cells help establish local conditions that suppress antitumour immunity to promote tumorigenesis. Here, we review evidence that Trp and Arg catabolism contributes to inflammatory processes that promote tumorigenesis, impede immune responses to therapy and might promote neurological comorbidities associated with cancer.

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Acknowledgements

Research in the A.L.M. and L.H. laboratory is supported by US National Institutes of Health (NIH) (AI103347), Cancer Research UK and the Faculty of Medical Sciences at Newcastle University. Research in the G.C.P. laboratory is supported by NIH (CA191191), the W.W. Smith Trust, the Lankenau Medical Center Foundation and Main Line Health. G.C.P. is the Havens Chair in Biomedical Research at the Lankenau Institute for Medical Research.

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Affiliations

  1. Institute of Cellular Medicine, Faculty of Medical Sciences, Framlington Place, Newcastle University, Newcastle-upon-Tyne, UK

    • Henrique Lemos
    • , Lei Huang
    •  & Andrew L. Mellor
  2. Lankenau Institute for Medical Research, Wynnewood, PA, USA

    • George C. Prendergast

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Contributions

All authors researched data for the article, substantially contributed to the discussion of content and wrote, reviewed and edited the manuscript.

Competing interests

A.L.M. and G.C.P. receive remuneration as scientific consultants for NewLink Genetics Inc. and are also shareholders in this company. G.C.P. also discloses interests in Incyte as a shareholder and in Kyn Therapeutics as a scientific adviser. A.L.M. also discloses interests as a scientific adviser to Kyn Therapeutics. The other authors declare no competing interests.

Corresponding author

Correspondence to Andrew L. Mellor.

Glossary

Immune checkpoints

Mechanisms that suppress local immunity in inflamed tissues such as the tumour microenvironment.

Immunological tumour microenvironment

(TME). Primary tumour lesions and local draining lymph nodes where antitumour immunity is controlled.

Integrated stress response

(ISR). A cellular response to stress that impacts protein translation via effects on the eukaryotic initiation factor eIF2.

Damage-associated molecular patterns

(DAMPs). Molecules released by dead and dying cells, which are sensed by innate immune cells.

M2 macrophages

A subset of macrophages typically associated with wound healing and tissue repair.

N-Methyl-d-aspartate receptor signalling

(NMDAR signalling). A signalling pathway that has dichotomous effects on neurons such as promoting death or survival of neurons, resistance to trauma and synaptic plasticity and transmission.

Mechanical nociception

Perception of pain in response to a mechanical stimulus.

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https://doi.org/10.1038/s41568-019-0106-z