Liver Immunology Laboratory, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui, China.
Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China.
Oncogene. 2018 Mar;37(9):1192-1204. doi: 10.1038/s41388-017-0048-4. Epub 2017 Dec 14.
Macrophages are a critical component in host immune responses against tumor. In this work we investigated the role of forkhead box O1 (FoxO1) in the transcriptional regulation in macrophages, which affects the anti-tumor functions of tumor-associated macrophages (TAMs). First, we showed that TAMs expressed reduced levels of FoxO1, which was associated with their protumoral M2 polarization state. The suppression of FoxO1 expression in TAM was induced by the hypoxic condition in the tumor microenviroment. Next, we confirmed that FoxO1 positively regulates MHC-II genes by binding to the promoter region of Ciita gene, the master activator of multiple MHC-II genes. Loss of FoxO1 in TAMs resulted in reduced MHC-II expression. Furthermore, we used FoxO1 conditional knockout mice to show that FoxO1 deficiency in myeloid cells exacerbates tumor growth. These results demonstrate that the protumoral property of TAMs is induced by the hypoxia-triggered FoxO1 deficiency, which could be a potential target of novel anti-tumor therapies.
巨噬细胞是宿主抗肿瘤免疫反应的关键组成部分。在这项工作中，我们研究了叉头框 O1（FoxO1）在调节巨噬细胞中的转录作用，这影响了肿瘤相关巨噬细胞（TAMs）的抗肿瘤功能。首先，我们表明 TAMs 表达的 FoxO1 水平降低，这与它们促进肿瘤的 M2 极化状态有关。TAM 中 FoxO1 表达的抑制是由肿瘤微环境中的缺氧条件诱导的。接下来，我们证实 FoxO1 通过与 MHC-II 基因的主激活子 Ciita 基因的启动子区域结合，正向调节 MHC-II 基因。TAMs 中 FoxO1 的缺失导致 MHC-II 表达减少。此外，我们使用 FoxO1 条件性敲除小鼠表明髓系细胞中 FoxO1 的缺失会加剧肿瘤生长。这些结果表明，TAMs 的促肿瘤特性是由缺氧触发的 FoxO1 缺失引起的，这可能是新型抗肿瘤治疗的潜在靶点。
