Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression
Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression
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DOI：
10.1016/j.cmet.2019.02.016
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发表时间：
2019-06-04
期刊：
影响因子：
29
通讯作者：
Lawrence, Toby
中科院分区：
文献类型：
--
作者：
Goossens, Pieter;Rodriguez-Vita, Juan;Lawrence, Toby
巨噬细胞具有内在的杀肿瘤活性，然而肿瘤相关巨噬细胞（TAM）在肿瘤微环境内迅速采用以肿瘤促进免疫抑制和营养功能为标志的替代表型。促进这种TAM极化的机制仍然知之甚少，但一旦确定，它们可能代表重要的治疗靶点，可以阻断TAM的促肿瘤功能并恢复其抗肿瘤潜力。在这里，我们已经在转移性卵巢癌的小鼠模型中表征了TAM。我们发现，卵巢癌细胞促进膜胆固醇流出和消耗的脂筏从巨噬细胞。增加胆固醇流出促进IL-4介导的重编程，包括抑制IFN γ诱导的基因表达。介导胆固醇流出的ABC转运蛋白的基因缺失可逆转TAM的促肿瘤功能并减少肿瘤进展。这些研究揭示了膜胆固醇流出在驱动TAM介导的肿瘤进展中的意想不到的作用，同时指出了一种潜在的新型抗肿瘤治疗策略。
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.