University of Bonn, LIMES Institute, Genomics and Immunoregulation; German Center for Neurodegenerative Diseases (DZNE) - Platform for Single Cell Genomics and Epigenomics (PRECISE)
Tumor-associated macrophages (TAM) have been shown to have important roles in the malignant progression of various cancers. However, macrophages also posses intrinsic tumoricidal activity and can promote the activity of cytotoxic lymphocytes, but they rapidly adopt an alternative phenotype within tumors, associated with immune-suppression and trophic functions that support tumor growth. The mechanisms that promote TAM polarization in the tumor-microenvironment remain poorly understood, these mechanisms may represent important therapeutic targets to block the tumor-promoting functions of TAM and restore their anti-tumor potential. Here we have characterized TAM in a mouse model of metastatic ovarian cancer. We show that ovarian cancer cells promote membrane-cholesterol efflux and the depletion of lipid rafts from macrophages. Increased cholesterol efflux promoted IL-4 mediated reprogramming while inhibiting IFNγ-induced gene expression. These studies reveal an unexpected role for tumor-induced membrane-cholesterol efflux in driving the IL-4 signaling and the tumor-promoting functions of TAM, while rendering them refractory to pro-inflammatory stimuli. Thus, preventing cholesterol efflux in TAM could represent a novel therapeutic strategy to block pro-tumor functions and restore anti-tumor immunity.
Goossens, Pieter and Rodriguez-Vita, Juan and Etzerodt, Anders and Masse, Marion and Rastoin, Olivia and Gouirand, Victoire and Van Eck, Miranda and Ulas, Thomas and Papantonopoulou, Olympia and Bebien, Magali and Turner, Martin and Manh, Thien Phong Vu and Dalod, Marc and Auphan-Anezin, Nathalie and Schultze, Joachim L. and Lawrence, Toby, Tumor-Induced Cholesterol Efflux from Macrophages Drives IL-4 Mediated Reprogramming and Tumor Progression (November 13, 2018). Available at SSRN: https://ssrn.com/abstract=3283707 or http://dx.doi.org/10.2139/ssrn.3283707
This version of the paper has not been formally peer reviewed.
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