Immune control by amino acid catabolism during tumorigenesis and therapy

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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS

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Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS IMMUNOMETABOLISM OF REGULATORY T CELLS IN CANCER Article Open access 04 June 2025 MYELOID-DERIVED ITACONATE SUPPRESSES

CYTOTOXIC CD8+ T CELLS AND PROMOTES TUMOUR GROWTH Article 14 November 2022 IMMUNOMETABOLISM IN CANCER: BASIC MECHANISMS AND NEW TARGETING STRATEGY Article Open access 16 May 2024 REFERENCES

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13), 192 (2018). Google Scholar  Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Institute of

Cellular Medicine, Faculty of Medical Sciences, Framlington Place, Newcastle University, Newcastle-upon-Tyne, UK Henrique Lemos, Lei Huang & Andrew L. Mellor * Lankenau Institute for

Medical Research, Wynnewood, PA, USA George C. Prendergast Authors * Henrique Lemos View author publications You can also search for this author inPubMed Google Scholar * Lei Huang View

author publications You can also search for this author inPubMed Google Scholar * George C. Prendergast View author publications You can also search for this author inPubMed Google Scholar *

Andrew L. Mellor View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS All authors researched data for the article, substantially contributed to

the discussion of content and wrote, reviewed and edited the manuscript. CORRESPONDING AUTHOR Correspondence to Andrew L. Mellor. ETHICS DECLARATIONS 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. ADDITIONAL INFORMATION

PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. RELATED LINKS CLINICALTRIALS.GOV DATABASE:

http://clinicaltrials.gov/ KAPLAN–MEIER PLOTTER: http://kmplot.com/ THE HUMAN PROTEIN ATLAS: http://www.proteinatlas.org/ 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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