Castration-resistant prostate cancer (CRPC) is a lethal stage of disease in which androgen receptor (AR) signaling is persistent despite androgen deprivation therapy (ADT). Most studies have focused on investigating cell-autonomous alterations in CRPC, while the contributions of the tumor microenvironment are less well understood. Here we sought to determine the role of tumor-associated macrophages in CRPC, based upon their role in cancer progression and therapeutic resistance. In a syngeneic model that reflected the mutational landscape of CRPC, macrophage depletion resulted in a reduced transcriptional signature for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. As cholesterol is the precursor of the five major types of steroid hormones, we hypothesized that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Macrophage depletion reduced androgen levels within prostate tumors and restricted AR nuclear localization in vitro and in vivo . Macrophages were also cholesterol-rich and were able to transfer cholesterol to tumor cells in vitro . AR nuclear translocation was inhibited by activation of liver X receptor (LXR)-β, the master regulator of cholesterol homeostasis. Consistent with these data, macrophage depletion extended survival during ADT and the presence of macrophages correlated with therapeutic resistance in patient-derived explants. Taken together, these findings support the therapeutic targeting of macrophages in CRPC. Significance: These results suggest that macrophage-targeted therapies can be combined with androgen deprivation therapy to treat patients with prostate cancer by limiting cholesterol bioavailability and the production of intratumoral androgens. See related commentary by Al-Janabi and Lewis, [p. 5399][1] [1]: /lookup/volpage/81/5399?iss=21

中文翻译：

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巨噬细胞来源的胆固醇导致前列腺癌的治疗耐药性

去势抵抗性前列腺癌 (CRPC) 是一种致命的疾病阶段，尽管雄激素剥夺治疗 (ADT)，雄激素受体 (AR) 信号仍然持续存在。大多数研究都集中在研究 CRPC 中的细胞自主改变，而对肿瘤微环境的贡献知之甚少。在这里，我们试图根据肿瘤相关巨噬细胞在癌症进展和治疗耐药中的作用来确定肿瘤相关巨噬细胞在 CRPC 中的作用。在反映 CRPC 突变情况的同基因模型中，巨噬细胞耗竭导致类固醇和胆汁酸合成的转录特征降低，表明胆固醇代谢可能受到干扰。由于胆固醇是五种主要类固醇激素的前体，我们假设巨噬细胞正在调节前列腺肿瘤微环境中的雄激素生物合成。巨噬细胞耗竭降低了前列腺肿瘤内的雄激素水平，并限制了体外和体内的 AR 核定位。巨噬细胞也富含胆固醇，并且能够在体外将胆固醇转移到肿瘤细胞中。AR 核转位被肝脏 X 受体 (LXR)-β 的激活所抑制，肝脏 X 受体 (LXR)-β 是胆固醇稳态的主要调节剂。与这些数据一致，巨噬细胞耗竭延长了 ADT 期间的生存期，并且巨噬细胞的存在与患者来源的外植体中的治疗抗性相关。总之，这些发现支持了 CRPC 中巨噬细胞的治疗靶向。意义：这些结果表明，巨噬细胞靶向疗法可以与雄激素剥夺疗法相结合，通过限制胆固醇生物利用度和瘤内雄激素的产生来治疗前列腺癌患者。见 Al-Janabi 和 Lewis 的相关评论，[p. 5399][1][1]：/lookup/volpage/81/5399?iss=21