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

TY - JOUR

T1 - Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression

AU - Goossens, Pieter

AU - Rodriguez-Vita, Juan

AU - Etzerodt, Anders

AU - Masse, Marion

AU - Rastoin, Olivia

AU - Gouirand, Victoire

AU - Ulas, Thomas

AU - Papantonopoulou, Olympia

AU - Van Eck, Miranda

AU - Auphan-Anezin, Nathalie

AU - Bebien, Magali

AU - Verthuy, Christophe

AU - Vu Manh, Thien Phong

AU - Turner, Martin

AU - Dalod, Marc

AU - Schultze, Joachim L

AU - Lawrence, Toby

N1 - Copyright © 2019 Elsevier Inc. All rights reserved.

PY - 2019/6/4

Y1 - 2019/6/4

N2 - 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 IFNγ-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.

AB - 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 IFNγ-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.

KW - IL-4 signaling

KW - cholesterol efflux

KW - lipid rafts

KW - ovarian cancer

KW - tumor-associated macrophages

U2 - 10.1016/j.cmet.2019.02.016

DO - 10.1016/j.cmet.2019.02.016

M3 - Journal article

C2 - 30930171

SN - 1550-4131

VL - 29

SP - 1376-1389.e4

JO - Cell Metabolism

JF - Cell Metabolism

IS - 6

ER -