Pro-atherogenic high fat diet accelerates tumor growth in mice through activation of innate immunity

Abstract

Inflammation is a physiologic protective process triggered in response to injury or infection. When unresolved, inflammation often promotes the development of chronic pathologies such as cancer or atherosclerosis. In atherosclerosis, hypercholesterolemia-associated monocytosis drives plaque formation in mice. Epidemiologic and experimental studies have shown the involvement of dyslipidiemia and low-grade inflammation on the development of multiple cancers. Surprisingly, the link between atherosclerosis and cancer has not been studied in details. The objective of our study was to question whether a pro-atherogenic high fat diet (HFD) would modify the development of solid tumors. Our experimental approach was to feed mice susceptible to atherosclerosis with a classical HFD (15% fat, 1.25% cholesterol) or a chow diet for 2 weeks before induction of tumor development. We monitored tumor development every two days and analyzed the mechanistic events by in vitro and in vivo experiments. We found that the proatherogenic HFD accelerated the growth of several solid tumors (B16F10 and TC1) in C57Bl6 mice, independently of cholesterol levels. In contrast, the HFD induced a significant increase of myeloid cells number in circulation and in the tumor microenvironment (flow cytometry). We isolated (Miltenyi) and analyzed the phenotype (qPCR and ELISA) of tumor-infiltrating leukocytes (TILs). We found a rapid upregulation of IL-1beta and VEGFa expression and a downregulation of several inflammatory cytokines. The supernatant of TILs isolated from mice under HFD and cultured for 48 hours, failed to reduce tumor cell proliferation in vitro (tritiated thymidine) and absence of IL-1beta, or selective depletion of neutrophils protected mice against tumor acceleration under HFD. These data show that in the context of a proaterogenic HFD, neutrophils accumulate in the tumor microenvironment and switch toward an immunosuppressive phenotype, thus promoting the fast growing of tumors.