Tumor Cells Scavenge Cholesterol from Tumor-Associated Macrophages

Although macrophages are known to exhibit tumoricidal activity, tumor-associated macrophages (TAM) adopt alternative signaling mechanisms to promote tumor growth and suppress antitumor immune responses. Goossens and colleagues show that cancer cells actively promote plasma membrane cholesterol efflux from TAMs, which enhances IL4 signaling and inhibits IFNγ-induced gene expression to contribute tumor progression. Seeding of ovarian cancer cells in the mouse peritoneal cavity was followed by blood monocyte–mediated, CCR2-dependent accumulation of peritoneal macrophages. Following tumor seeding, global gene-expression analysis of TAMs revealed upregulation of genes associated with IL4 signaling and cholesterol metabolism and efflux. Co-culture of bone marrow–derived macrophages (BMDM) with ovarian cancer cells or ovarian cancer cell–conditioned medium resulted in decreased cholesterol-rich membrane microdomains and a reduction in total cholesterol levels in BMDMs. Pretreatment of the conditioned medium with hyaluronidase (HAase) or deletion of the ABC transporter Abca1 in TAMs abrogated depletion of cholesterol in macrophages, indicating that active cholesterol efflux is responsible for the decrease in plasma membrane cholesterol levels. Following stimulation with IL4 or IFNγ, conditioned medium–pretreated BMDMs showed increased expression of IL4-induced genes and inhibited expression of IFNγ-induced genes. IL4 treatment also resulted in increased levels of activated STAT6 and phosphorylated AKT, and pharmacologic inhibition of PI3K abrogated these changes. Depletion of membrane cholesterol elicited similar effects, but not in cells lacking the ABC transporters or following incubation with HAase-treated conditioned medium. Inhibition of mTORC1 and mTORC2 also blocked phosphorylation of AKT, indicating that mTORC activity is required for macrophage reprogramming. In vivo, treatment with an IL4 receptor–blocking antibody or hematopoietic deficiency in Stat6, Pik3cd, or ABC receptors reduced ovarian cancer xenograft growth. Taken together, these data demonstrate that cholesterol efflux plays an important role in TAM reprogramming and tumor progression and may represent a potential therapeutic target.

Goossens P, Rodriguez-Vita J, Etzerodt A, Masse M, Rastoin O, Gouirand V, et al. Membrane cholesterol efflux drives tumor-associated macrophage reprogramming and tumor progression. Cell Metab 2019 Mar 28 [Epub ahead of print].

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