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

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

doi: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+ 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.

Highlights

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
Very little is known about neutrophil mitochondrial activity and how it may relate to their developmental state or function in different tissue settings
As bone marrow is the primary site of haematopoiesis, we hypothesised that elevated mitochondrial capacity might be related to an immature phenotype

Summary

Introduction

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. MDSC function was shown to have specific metabolic underpinnings, with tumour-associated MDSC exhibiting increased fatty acid oxidation and mitochondrial function that correlated with immunosuppressive capacity[26] These studies did not define the MDSC sub-populations, dissect how mitochondrial function was enhanced or delineate how it contributed to the suppressive action of these cells. Our data suggest that oxidative neutrophils benefit tumour growth as, unlike glycolytic-neutrophils from a healthy host, they can maintain ROS-mediated suppression of T cells even in the nutrient limited TME. These data shed new light on the role of mitochondria in phagocyte function and suggest that neutrophil mitochondrial metabolism could prove an effective target for cancer therapy

Methods

Results

Conclusion