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Aims: Myeloid inflammatory cells are recruited to the tumor microenvironment and subsequently educated in situ to acquire a pro-invasive, pro-angiogenic and immunosuppressive phenotype. Components of the metabolic syndrome are known to aggravate tumorigenesis in part through myeloid cell activation. We hypothesized that consumption of a high fat/high cholesterol pro-atherogenic diet and its associated low-grade inflammation would accelerate the initiation of solid tumors. Methods and results: Here, we show that two-week feeding of wildtype C57BL/6J mice with a pro-atherogenic diet increases the pool of circulating inflammatory Ly-6Chi monocytes available for initial melanoma development and amplifies the accumulation of myeloid cells within the tumor microenvironment, in an IL-1β-dependent manner. Under pro-atherogenic diet feeding, myeloid cells display heightened pro-angiogenic, pro-inflammatory and immunosuppressive activities. Within the first days after tumor implantation, myeloid cells become the main producer of VEGF-A in the tumor. Depletion of Ly-6Chi monocytes in mice fed with a pro-atherogenic diet limits immune cell infiltration in the tumor, and inhibits tumor growth. IL-1β deficiency or specific inhibition of VEGF-A in myeloid cells recapitulates the beneficial effect of Ly-6Chi monocyte depletion, suggesting their complementary roles in tumorigenesis in the context of mild hyperlipidemia. Conclusion: Our study shows that dyslipidemia provide high amounts of activated myeloid cells with pro-tumoral activity and shed light on cross-disease communication between cardiovascular pathologies and cancer. Translational Perspective: In this study we demonstrate that dyslipidemia accelerates the development of solid tumors through the increased infiltration of Ly6Chi monocytes that differentiate into pro-tumoral myeloid cells. These findings demonstrate that dyslipidemia can silently boost tumor development in normal-weight individuals through the action of IL-1β and VEGF-A. Our work sheds light on the potential benefit of targeting IL-1β and VEGF-A in cancer patients with moderate dyslipidemia.

Cancer and cardiovascular disease (CVD) share common risk factors such as dyslipidemia, obesity and inflammation. However, the role of pro-atherogenic environment and its associated low-grade inflammation in tumor progression remains underexplored. Here we show that feeding C57BL/6J mice with a non-obesogenic high fat high cholesterol diet (HFHCD) for two weeks to induce mild dyslipidemia, increases the pool of circulating Ly6C