Cancer Gene Therapy Unit, Program of Immunology and Bio Immuno Gene Therapy of Cancer, Division of Molecular Oncology, Scientific Institute San Raffaele, Milan, Italy.
Nat Med. 2010 Jan;16(1):98-105. doi: 10.1038/nm.2074. Epub 2009 Dec 27.
Sterol metabolism has recently been linked to innate and adaptive immune responses through liver X receptor (LXR) signaling. Whether products of sterol metabolism interfere with antitumor responses is currently unknown. Dendritic cells (DCs) initiate immune responses, including antitumor activity after their CC chemokine receptor-7 (CCR7)-dependent migration to lymphoid organs. Here we report that human and mouse tumors produce LXR ligands that inhibit CCR7 expression on maturing DCs and, therefore, their migration to lymphoid organs. In agreement with this observation, we detected CD83(+)CCR7(-) DCs within human tumors. Mice injected with tumors expressing the LXR ligand-inactivating enzyme sulfotransferase 2B1b (SULT2B1b) successfully controlled tumor growth by regaining DC migration to tumor-draining lymph nodes and by developing overt inflammation within tumors. The control of tumor growth was also observed in chimeric mice transplanted with bone marrow from mice lacking the gene encoding LXR-alpha (Nr1h3(-/-) mice) Thus, we show a new mechanism of tumor immunoescape involving products of cholesterol metabolism. The manipulation of this pathway could restore antitumor immunity in individuals with cancer.
固醇代谢最近通过肝 X 受体 (LXR) 信号与先天和适应性免疫反应联系起来。固醇代谢产物是否干扰抗肿瘤反应目前尚不清楚。树突状细胞 (DC) 在其 CC 趋化因子受体-7 (CCR7) 依赖性迁移到淋巴器官后，会引发免疫反应，包括抗肿瘤活性。在这里，我们报告人类和小鼠肿瘤产生 LXR 配体，抑制成熟 DC 上的 CCR7 表达，从而抑制其向淋巴器官的迁移。与这一观察结果一致，我们在人类肿瘤中检测到 CD83(+)CCR7(-) DC。用表达 LXR 配体失活酶磺基转移酶 2B1b (SULT2B1b) 的肿瘤注射的小鼠通过恢复 DC 向肿瘤引流淋巴结的迁移并在肿瘤内引发明显炎症，成功控制了肿瘤生长。在从缺乏编码 LXR-α 的基因的小鼠 (Nr1h3(-/-) 小鼠) 中移植骨髓的嵌合小鼠中也观察到了对肿瘤生长的控制。因此，我们展示了一种涉及胆固醇代谢产物的肿瘤免疫逃避的新机制。对该途径的操纵可以恢复癌症患者的抗肿瘤免疫。
