CNRS, Aix Marseille University, INSERM, CIML, Marseille 13009, France; Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, 6229HX Maastricht, the Netherlands.
CNRS, Aix Marseille University, INSERM, CIML, Marseille 13009, France; Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
Cell Metab. 2019 Jun 4;29(6):1376-1389.e4. doi: 10.1016/j.cmet.2019.02.016. Epub 2019 Mar 28.
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.
巨噬细胞具有内在的杀瘤活性，但肿瘤相关巨噬细胞（TAMs）在肿瘤微环境中迅速转变为另一种表型，其特征是具有促进肿瘤的免疫抑制和营养功能。促进这种 TAM 极化的机制仍知之甚少，但一旦确定，它们可能成为重要的治疗靶点，以阻断 TAMs 的促肿瘤功能并恢复其抗肿瘤潜能。在这里，我们在转移性卵巢癌的小鼠模型中对 TAMs 进行了表征。我们表明，卵巢癌细胞促进巨噬细胞中膜胆固醇外流和脂筏耗竭。增加的胆固醇外流促进了 IL-4 介导的重编程，包括抑制 IFNγ 诱导的基因表达。介导胆固醇外流的 ABC 转运体的基因缺失可逆转 TAMs 的促肿瘤功能并减少肿瘤进展。这些研究揭示了膜胆固醇外流在驱动 TAM 介导的肿瘤进展中的意外作用，同时指出了一种潜在的新型抗肿瘤治疗策略。
