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

Christopher M. Rice (), Luke C. 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 and Daniel W. McVicar ()
Additional contact information
Christopher M. Rice: National Cancer Institute
Luke C. Davies: National Cancer Institute
Jeff J. Subleski: National Cancer Institute
Nunziata Maio: National Institute of Health
Marieli Gonzalez-Cotto: National Cancer Institute
Caroline Andrews: National Cancer Institute
Nimit L. Patel: National Cancer Institute
Erika M. Palmieri: National Cancer Institute
Jonathan M. Weiss: National Cancer Institute
Jung-Min Lee: National Cancer Institute
Christina M. Annunziata: National Cancer Institute
Tracey A. Rouault: National Institute of Health
Scott K. Durum: National Cancer Institute
Daniel W. McVicar: National Cancer Institute

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07505-2

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