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Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression

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Goossens, Pieter | Rodriguez-Vita, Juan | Etzerodt, Anders | Massé, Marion | Rastoin, Olivia | Gouirand, Victoire | Ulas, Thomas | Papantonopoulou, Olympia | van Eck, Miranda | Auphan-Anezin, Nathalie | Bebien, Magali | Verthuy, Christophe | Manh, Thien Phong Vu | Turner, Martin | Dalod, Marc | Schultze, Joachim L. | Lawrence, Toby

Edité par CCSD ; Elsevier -

International audience. Macrophages possess intrinsic tumoricidal activity, yet tumor-associated macrophages (TAMs) rapidly adopt an alternative phenotype within the tumor microenvironment that is marked by tumor-promoting immunosuppressive and trophic functions. The mechanisms that promote such TAM polarization remain poorly understood, but once identified, they may represent important therapeutic targets to block the tumor-promoting functions of TAMs and restore their anti-tumor potential. Here, we have characterized TAMs in a mouse model of metastatic ovarian cancer. We show that ovarian cancer cells promote membrane cholesterol efflux and depletion of lipid rafts from macrophages. Increased cholesterol efflux promoted IL-4-mediated reprogramming, including inhibition of IFN gamma-induced gene expression. Genetic deletion of ABC transporters, which mediate cholesterol efflux, reverts the tumor-promoting functions of TAMs and reduces tumor progression. These studies reveal an unexpected role for membrane-cholesterol efflux in driving TAM-mediated tumor progression while pointing to a potentially novel anti-tumor therapeutic strategy.

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