艾克斯马赛大学Toby Lawrence团队近日取得一项新成果。研究认为，膜胆固醇外排驱使肿瘤相关巨噬细胞重新编程和肿瘤发展。该成果发表在2019年6月4日出版的国际学术期刊《Cell Metabolism》上。

课题组通过转移性卵巢癌的小鼠模型，对肿瘤相关巨噬细胞（TAMs）展开了深入研究。研究者发现卵巢癌细胞能够促进巨噬细胞内细胞膜胆固醇的外排和脂筏的消耗。增加胆固醇外排能够促进白细胞介素4（IL4）介导的重编程，抑制干扰素γ诱导的基因表达。研究者发现介导胆固醇外排的ABC转运体基因缺失后，TAMs的肿瘤促进功能得到减弱，并延缓了肿瘤的进展。这些研究揭示了膜胆固醇外排在TAM介导的肿瘤进展中的一个意想不到的作用，同时指出了一种潜在的新的抗肿瘤治疗策略。

据了解，巨噬细胞本身具有抑制和消灭肿瘤的活性，但肿瘤相关巨噬细胞(TAMs)在肿瘤微环境中迅速分化为另一种表型，起到提高肿瘤免疫抑制能力和提供营养的功能。促进TAMs发生该分化的机制尚不清楚，然而一旦确定，它们则可能成为重要的肿瘤治疗靶标，能够有效阻断TAMs促肿瘤功能并恢复其抗肿瘤潜能。

附：英文原文

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

Author: Pieter Goossens, Juan Rodriguez-Vita, Anders Etzerodt, Marc Dalod, Joachim L. Schultze, Toby Lawrence

Issue&Volume: Jun 04, 2019 Volume 29Issue 6

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.

DOI: https://doi.org/10.1016/j.cmet.2019.02.016

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30128-7