Early Neutrophilia Marked by Aerobic Glycolysis Sustains Host Metabolism and Delays Cancer Cachexia

SIMPLE SUMMARY: Patients with cancer suffer from systemic metabolic impairment during cancer progression. An elevated neutrophil–lymphocyte ratio is a negative predictor of outcome. In the present study, we investigate a potential role of neutrophils on host metabolism. We identified widespread neutrophilia as an early event in cancer progression and found that neutrophils display an enhanced aerobic glycolytic profile. Pharmacological inhibition of aerobic glycolysis, a pathway that also characterizes cancer cells, leads to expanded neutrophilia, reduced tumor size, and shorter survival. Quantitative depletion of neutrophils impairs glucose homeostasis and the availability of hepatic lipids. Our results suggest that neutrophils play an adaptive role in metabolic host homeostasis during cancer progression and demonstrate that assessment of candidate cancer treatment efficacy should include both tumor and host responses. ABSTRACT: An elevated neutrophil–lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, using murine model systems of colorectal and pancreatic cancer we show that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, similar to cancer cells. Although pharmacological inhibition of aerobic glycolysis slows down tumor growth in C26 tumor-bearing mice, it precipitates cachexia, thereby shortening the overall survival. This negative effect may be explained by our observation that acute depletion of neutrophils in pre-cachectic mice impairs systemic glucose homeostasis secondary to altered hepatic lipid processing. Thus, changes in neutrophil number, distribution, and metabolism play an adaptive role in host metabolic homeostasis during cancer progression. Our findings provide insight into early events during cancer progression to cachexia, with implications for therapy.