Cutting edge: Hypoxia-induced Nanog favors the intratumoral infiltration of regulatory T cells and macrophages via direct regulation of TGF-β1.

Abstract

Emerging evidence suggests a link between tumor hypoxia and immune suppression. In this study, we investigated the role of hypoxia-induced Nanog, a stemness-associated transcription factor, in immune suppression. We observed that hypoxia-induced Nanog correlated with the acquisition of stem cell-like properties in B16-F10 cells. We further show that Nanog was selectively induced in hypoxic areas of B16-F10 tumors. Stable short hairpin RNA-mediated depletion of Nanog, combined with melanocyte differentiation Ag tyrosinase-related protein-2 peptide-based vaccination, resulted in complete inhibition of B16-F10 tumor growth. Nanog targeting significantly reduced immunosuppressive cells (regulatory T cells and macrophages) and increased CD8(+) T effector cells in tumor bed in part by modulating TGF-β1 production. Additionally, Nanog regulated TGF-β1 under hypoxia by directly binding the TGF-β1 proximal promoter. Collectively, our data establish a novel functional link between hypoxia-induced Nanog and TGF-β1 regulation and point to a major role of Nanog in hypoxia-driven immunosuppression.

• Authors: Meriem Hasmim, Muhammad Zaeem Noman, Yosra Messai, Didier Bordereaux, Gwendoline Gros, Veronique Baud, Salem Chouaib
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 191 Issue 12 Pg. 5802-6 (Dec 15 2013) ISSN: 1550-6606 [Electronic] United States
• PMID: 24227785 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Homeodomain Proteins
• Nanog Homeobox Protein
• Nanog protein, mouse
• Neoplasm Proteins
• Peptide Fragments
• RNA, Small Interfering
• Transforming Growth Factor beta1
• Intramolecular Oxidoreductases
• dopachrome isomerase

Topics

• Animals
• Cell Hypoxia (genetics)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Genetic Therapy
• Homeodomain Proteins (antagonists & inhibitors, biosynthesis, genetics, physiology)
• Immunotherapy
• Intramolecular Oxidoreductases (immunology)
• Lymphocytes, Tumor-Infiltrating (immunology)
• Lymphopoiesis
• Macrophages (immunology)
• Melanoma, Experimental (genetics, immunology, metabolism, therapy)
• Mice, Inbred C57BL
• Nanog Homeobox Protein
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, genetics, physiology)
• Neoplastic Stem Cells (cytology, enzymology, immunology)
• Peptide Fragments (immunology)
• Promoter Regions, Genetic
• RNA Interference
• RNA, Small Interfering
• Spheroids, Cellular
• T-Lymphocytes, Regulatory (immunology)
• Transforming Growth Factor beta1 (biosynthesis, genetics, metabolism, physiology)
• Tumor Escape (genetics, immunology)
• Tumor Microenvironment
• Up-Regulation
• Vaccination