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

Jing-Bo Yang; Zhi-Bin Zhao; Qing-Zhi Liu; Tai-Dou Hu; Jie Long; Kai Yan; Zhe-Xiong Lian

doi:10.1038/s41388-017-0048-4

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

Oncogene. 2018 Mar;37(9):1192-1204. doi: 10.1038/s41388-017-0048-4. Epub 2017 Dec 14.

Authors

Jing-Bo Yang¹, Zhi-Bin Zhao^{1

2}, Qing-Zhi Liu^{1

2}, Tai-Dou Hu^{1

2}, Jie Long^{1

2}, Kai Yan^{1

2}, Zhe-Xiong Lian^{3

4

5}

Affiliations

¹ 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.
² Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China.
³ 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. [email protected].
⁴ Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China. [email protected].
⁵ Innovation Center for Cell Signaling Network, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China. [email protected].

PMID: 29238041
DOI: 10.1038/s41388-017-0048-4

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.

MeSH terms

Animals
Apoptosis
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism*
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology*
Cell Proliferation
Colonic Neoplasms / genetics
Colonic Neoplasms / metabolism
Colonic Neoplasms / pathology
Forkhead Box Protein O1 / genetics
Forkhead Box Protein O1 / metabolism*
Forkhead Box Protein O1 / physiology*
Gene Expression Regulation, Neoplastic
Genes, MHC Class II*
Humans
Hypoxia / physiopathology
Liver Neoplasms / genetics
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Macrophages / metabolism
Macrophages / pathology*
Melanoma / genetics
Melanoma / metabolism
Melanoma / pathology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Prognosis
Promoter Regions, Genetic
Skin Neoplasms / genetics
Skin Neoplasms / metabolism
Skin Neoplasms / pathology
Trans-Activators / genetics
Trans-Activators / metabolism
Tumor Cells, Cultured

Substances

Biomarkers, Tumor
FOXO1 protein, human
Forkhead Box Protein O1
Foxo1 protein, mouse
MHC class II transactivator protein
Nuclear Proteins
Trans-Activators