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α 1 -Acid Glycoprotein Enhances the Immunosuppressive and Protumor Functions of Tumor-Associated Macrophages.
α 1 -Acid Glycoprotein Enhances the Immunosuppressive and Protumor Functions of Tumor-Associated Macrophages.
- Source :
-
Cancer research [Cancer Res] 2021 Sep 01; Vol. 81 (17), pp. 4545-4559. Date of Electronic Publication: 2021 Jul 01. - Publication Year :
- 2021
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Abstract
- Blood levels of acute-phase protein α <subscript>1</subscript> -acid glycoprotein (AGP, orosmucoid) increase in patients with cancer. Although AGP is produced from hepatocytes following stimulation by immune cell-derived cytokines under conditions of inflammation and tumorigenesis, the functions of AGP in tumorigenesis and tumor progression remain unknown. In the present study, we revealed that AGP contributes directly to tumor development by induction of programmed death ligand 1 (PD-L1) expression and IL6 production in macrophages. Stimulation of AGP induced PD-L1 expression in both human monocyte-derived macrophages through STAT1 activation, whereas AGP had no direct effect on PD-L1 expression in tumor cells. AGP also induced IL6 production from macrophages, which stimulated proliferation in tumor cells by IL6R-mediated activation of STAT3. Furthermore, administration of AGP to AGP KO mice phenocopied effects of tumor-associated macrophages (TAM) on tumor progression. AGP decreased IFNγ secretion from T cells and enhanced STAT3 activation in subcutaneous tumor tissues. In addition, AGP regulated PD-L1 expression and IL6 production in macrophages by binding with CD14, a coreceptor for Toll-like receptor 4 (TLR4), and inducing TLR4 signaling. These results provide the first evidence that AGP is directly involved in tumorigenesis by interacting with TAMs and that AGP might be a target molecule for anticancer therapy. SIGNIFICANCE: AGP-mediated suppression of antitumor immunity contributes to tumor progression by inducing PD-L1 expression and IL6 production in TAMs.<br /> (©2021 American Association for Cancer Research.)
- Subjects :
- Animals
Carcinogenesis
Cell Proliferation
Disease Progression
Enhancer Elements, Genetic
Hepatocytes metabolism
Immunosuppression Therapy
Interferon-gamma metabolism
Macrophages cytology
Membrane Proteins
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Knockout
Monocytes cytology
Orosomucoid genetics
Signal Transduction
Toll-Like Receptor 4 metabolism
B7-H1 Antigen metabolism
Macrophages metabolism
Orosomucoid metabolism
Tumor-Associated Macrophages metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 81
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 34210751
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-20-3471