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

• DOI: 10.1016/j.cmet.2019.02.016
• Publication Date: 2019-03-28T14:35:12Z
• Authors: Pieter Goossens; Juan Rodriguez-Vita; Anders Etzerodt; Marion Masse; Olivia Rastoin; Victoire Gouirand; Thomas Ulas; Olympia Papantono...; Miranda Van Eck; Nathalie Auphan-A...; Magali Bebien; Christophe Verthuy; Thien Phong Vu Manh; Martin Turner; Marc Dalod; Joachim L. Schultze; Toby Lawrence
• Keywords: 0301 basic medicine; pathology [Bone Marrow Cells]; Expression; physiology [Tumor Microenvironment]; Monocytes; Mice; Neoplasms; Tumor Microenvironment; Cholesterol efflux; MYELOID CELLS; Hyaluronan; Cells, Cultured; lipid rafts; IL-4 signaling; tumor-associated macrophages; Tumor-associated macrophages; PI3K-GAMMA; pathology [Neoplasms]; Tissue macrophages; Cellular Reprogramming; physiology [Biological Transport]; Pi3k-gamma; 3. Good health; ovarian cancer; metabolism [ATP-Binding Cassette Transporters]; Cholesterol; MONOCYTES; metabolism [Neoplasms]; physiology [Bone Marrow Cells]; physiology [Cellular Reprogramming]; Myeloid cells; Disease Progression; [SDV.IMM]Life Sciences [q-bio]/Immunology; TISSUE MACROPHAGES; Female; EXPRESSION; HYALURONAN; 610; [SDV.CAN]Life Sciences [q-bio]/Cancer; Bone Marrow Cells; Mice, Transgenic; metabolism [Cell Membrane]; immunology [Neoplasms]; 03 medical and health sciences; Ovarian cancer; ddc:570; 616; Animals; tumor-associated macrophages.; Lipid rafts; Macrophages; Cell Membrane; Biological Transport; physiology [Macrophages]; metabolism [Cholesterol]; physiology [Tumor Escape]; Mice, Inbred C57BL; ATP-Binding Cassette Transporters; Tumor Escape; genetics [ATP-Binding Cassette Transporters]; cholesterol efflux

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.