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FoxO1 is a regulator of MHC-II expression and anti-tumor effect of tumor-associated macrophages

Abstract

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.

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Acknowledgements

We gratefully thank Dr. Xiao-Song He for discussion and linguistic revision of the manuscript. We also thank Dr. Ping Gao, Dr. Hua-Feng Zhang, and Dr. Mian Wu for their technical support.

Funding

Funding

This work was supported by the National Natural Science Foundation of China under Grant 81430034 and 91542123; National Basic Research Program of China under Grant 973 Program-2013CB944900.

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Correspondence to Zhe-Xiong Lian.

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Jing-Bo Yang and Zhi-Bin Zhao contributed equally to this work.

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Yang, JB., Zhao, ZB., Liu, QZ. et al. FoxO1 is a regulator of MHC-II expression and anti-tumor effect of tumor-associated macrophages. Oncogene 37, 1192–1204 (2018). https://doi.org/10.1038/s41388-017-0048-4

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