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Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression

Christopher M. Rice, Luke Davies Orcid Logo, Jeff J. Subleski, Nunziata Maio, Marieli Gonzalez-Cotto, Caroline Andrews, Nimit L. Patel, Erika M. Palmieri, Jonathan M. Weiss, Jung-Min Lee, Christina M. Annunziata, Tracey A. Rouault, Scott K. Durum, Daniel W. McVicar

Nature Communications, Volume: 9, Issue: 1

Swansea University Author: Luke Davies Orcid Logo

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DOI (Published version): 10.1038/s41467-018-07505-2

Abstract

Neutrophils are a vital component of immune protection, yet in cancer they may promote tumour progression, partly by generating reactive oxygen species (ROS) that disrupts lymphocyte functions. Metabolically, neutrophils are often discounted as purely glycolytic. Here we show that immature, c-Kit+ n...

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Published in: Nature Communications
ISSN: 2041-1723
Published: Springer Science and Business Media LLC 2018
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URI: https://cronfa.swan.ac.uk/Record/cronfa61701
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spelling 2022-11-07T12:32:44.3867715 v2 61701 2022-10-31 Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression ff080296775381560053d5e3a6e81745 0000-0001-7767-4060 Luke Davies Luke Davies true false 2022-10-31 MEDS Neutrophils are a vital component of immune protection, yet in cancer they may promote tumour progression, partly by generating reactive oxygen species (ROS) that disrupts lymphocyte functions. Metabolically, neutrophils are often discounted as purely glycolytic. Here we show that immature, c-Kit+ neutrophils subsets can engage in oxidative mitochondrial metabolism. With limited glucose supply, oxidative neutrophils use mitochondrial fatty acid oxidation to support NADPH oxidase-dependent ROS production. In 4T1 tumour-bearing mice, mitochondrial fitness is enhanced in splenic neutrophils and is driven by c-Kit signalling. Concordantly, tumour-elicited oxidative neutrophils are able to maintain ROS production and T cell suppression when glucose utilisation is restricted. Consistent with these findings, peripheral blood neutrophils from patients with cancer also display increased immaturity, mitochondrial content and oxidative phosphorylation. Together, our data suggest that the glucose-restricted tumour microenvironment induces metabolically adapted, oxidative neutrophils to maintain local immune suppression. Journal Article Nature Communications 9 1 Springer Science and Business Media LLC 2041-1723 30 11 2018 2018-11-30 10.1038/s41467-018-07505-2 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University This work has been funded with federal funds from the National Cancer Institute, National Institutes of Health, Intramural Research Program, USA. L.C.D. is funded by the Henry Wellcome Trust, UK (WT103973MA). 2022-11-07T12:32:44.3867715 2022-10-31T12:39:11.3925001 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Christopher M. Rice 1 Luke Davies 0000-0001-7767-4060 2 Jeff J. Subleski 3 Nunziata Maio 4 Marieli Gonzalez-Cotto 5 Caroline Andrews 6 Nimit L. Patel 7 Erika M. Palmieri 8 Jonathan M. Weiss 9 Jung-Min Lee 10 Christina M. Annunziata 11 Tracey A. Rouault 12 Scott K. Durum 13 Daniel W. McVicar 14 61701__25667__83b32f65065b47a690a5813471d8c3fe.pdf 61701.pdf 2022-11-07T12:31:10.3817637 Output 1842660 application/pdf Version of Record true © The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License true eng http://creativecommons.org/licenses/by/4.0/
title Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression
spellingShingle Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression
Luke Davies
title_short Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression
title_full Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression
title_fullStr Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression
title_full_unstemmed Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression
title_sort Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression
author_id_str_mv ff080296775381560053d5e3a6e81745
author_id_fullname_str_mv ff080296775381560053d5e3a6e81745_***_Luke Davies
author Luke Davies
author2 Christopher M. Rice
Luke Davies
Jeff J. Subleski
Nunziata Maio
Marieli Gonzalez-Cotto
Caroline Andrews
Nimit L. Patel
Erika M. Palmieri
Jonathan M. Weiss
Jung-Min Lee
Christina M. Annunziata
Tracey A. Rouault
Scott K. Durum
Daniel W. McVicar
format Journal article
container_title Nature Communications
container_volume 9
container_issue 1
publishDate 2018
institution Swansea University
issn 2041-1723
doi_str_mv 10.1038/s41467-018-07505-2
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
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description Neutrophils are a vital component of immune protection, yet in cancer they may promote tumour progression, partly by generating reactive oxygen species (ROS) that disrupts lymphocyte functions. Metabolically, neutrophils are often discounted as purely glycolytic. Here we show that immature, c-Kit+ neutrophils subsets can engage in oxidative mitochondrial metabolism. With limited glucose supply, oxidative neutrophils use mitochondrial fatty acid oxidation to support NADPH oxidase-dependent ROS production. In 4T1 tumour-bearing mice, mitochondrial fitness is enhanced in splenic neutrophils and is driven by c-Kit signalling. Concordantly, tumour-elicited oxidative neutrophils are able to maintain ROS production and T cell suppression when glucose utilisation is restricted. Consistent with these findings, peripheral blood neutrophils from patients with cancer also display increased immaturity, mitochondrial content and oxidative phosphorylation. Together, our data suggest that the glucose-restricted tumour microenvironment induces metabolically adapted, oxidative neutrophils to maintain local immune suppression.
published_date 2018-11-30T14:25:01Z
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