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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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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
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa61701
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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+ 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.
College: Faculty of Medicine, Health and Life Sciences
Funders: 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).
Issue: 1