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

Abstract

Abstract Neutrophils are a vital component of the immune system, however in cancer they often play major roles in tumour progression, partly by generating reactive oxygen species (ROS) which disrupts lymphocyte function. Metabolically, neutrophils are often overlooked as purely glycolytic, however we show that immature subsets, defined by c-Kit expression, possess the capacity for oxidative mitochondrial metabolism. In limited glucose, oxidative neutrophils use mitochondrial fatty acid oxidation to fuel NADPH-oxidase (NOX) dependent ROS production. In 4T1 tumour bearing mice, mitochondrial fitness is enhanced in circulating and splenic neutrophils and is associated with the expression of c-Kit. Concordantly, tumour-elicited oxidative neutrophils are able to maintain ROS production and suppression of T-cell when glucose utilization is restricted. In accordance with these findings, peripheral blood neutrophils from cancer patient are more immature, with increased mitochondrial content and higher subsequent oxidative phosphorylation. Together our data suggest that tumours elicit oxidative neutrophil populations which are adapted to maintain immune-suppressive activity in the glucose-restricted tumour microenvironment.