@article{bf5518eed57e4672816b857c2e957886,
title = "Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression",
abstract = "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. Goossens, Rodriguez-Vita et al. show that cancer cells scavenge membrane cholesterol from tumor-associated macrophages, resulting in their reprogramming toward an immune-suppressive and tumor-promoting phenotype. Targeting cholesterol efflux in macrophages counters this reprogramming and reduces tumor progression in a model of ovarian cancer.",
keywords = "TISSUE MACROPHAGES, MYELOID CELLS, HYALURONAN, EXPRESSION, MONOCYTES, PI3K-GAMMA, Hyaluronan, Tissue macrophages, Myeloid cells, Monocytes, Expression, Pi3k-gamma",
author = "Pieter Goossens and Juan Rodriguez-Vita and Anders Etzerodt and Marion Masse and Olivia Rastoin and Victoire Gouirand and Thomas Ulas and Olympia Papantonopoulou and \{Van Eck\}, Miranda and Nathalie Auphan-Anezin and Magali Bebien and Christophe Verthuy and \{Thien Phong Vu Manh\} and Martin Turner and Marc Dalod and Schultze, \{Joachim L.\} and Toby Lawrence",
note = "Funding Information: We thank Bernard Malissen (CIML, FR) for Stat −/− mice. These studies were supported by grants to T.L. from L{\textquoteright}Agence Nationale de la Recherche (ANR); ANR-09-MIEN-029-01 , ANR-10-BLAN-1302-01 , and European Research Council ; FP7/2007–2013 grant agreement number 260753; and institutional funding from INSERM , CNRS , and Aix-Marseille-Universit{\'e} . J.R.-V. was funded by Marie Curie actions IEF (no. 234823 ). P.G. was funded by the French Ligue Nationale contre le Cancer (LNCC). A.E. was funded by the Novo Nordisk Foundation ( NNF14OC0008781 ). Microscopy facilities are supported by ANR-10-INBS-04-01 France Bio Imaging. J.L.S. is a member of the Excellence Cluster ImmunoSensation. The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union{\textquoteright}s Seventh Framework Programme FP7/2077-2013 under REA grant agreement no. 317445 to J.L.S. Funding Information: We thank Bernard Malissen (CIML, FR) for Stat−/− mice. These studies were supported by grants to T.L. from L'Agence Nationale de la Recherche (ANR); ANR-09-MIEN-029-01, ANR-10-BLAN-1302-01, and European Research Council; FP7/2007–2013 grant agreement number 260753; and institutional funding from INSERM, CNRS, and Aix-Marseille-Universit{\'e}. J.R.-V. was funded by Marie Curie actions IEF (no.234823). P.G. was funded by the French Ligue Nationale contre le Cancer (LNCC). A.E. was funded by the Novo Nordisk Foundation (NNF14OC0008781). Microscopy facilities are supported by ANR-10-INBS-04-01 France Bio Imaging. J.L.S. is a member of the Excellence Cluster ImmunoSensation. The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7/2077-2013 under REA grant agreement no. 317445 to J.L.S. P.G. J.R.-V. A.E. and T.L. designed the experiments. P.G. J.R.-V. and A.E. performed the experiments with help from O.R. V.G. C.V. M.B. and N.A.-A. Bioinformatics analysis was performed by M.M. T.P.V.M. M.D. O.P. T.U. and J.L.S. M.V.E. performed cholesterol efflux assays. M.T. provided Pik3cd−/− mice. P.G. J.R.-V. A.E. and T.L. wrote the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = jun,
day = "4",
doi = "10.1016/j.cmet.2019.02.016",
language = "English",
volume = "29",
pages = "1376--1389.e4",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "6",
}