Cutting edge: Hypoxia-induced Nanog favors the intratumoral infiltration of regulatory T cells and macrophages via direct regulation of TGF-β1.
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.
INSERM Unité 753, Institut Gustave Roussy, 94800 Villejuif, France.
Meriem
M
Hasmim
Muhammad Zaeem
MZ
Noman
Yosra
Y
Messai
Didier
D
Bordereaux
Gwendoline
G
Gros
Veronique
V
Baud
Salem
S
Chouaib
D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007167:Immunotherapy; D019746:Intramolecular Oxidoreductases / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D038041:Lymphopoiesis; D008264:Macrophages / Q000276:immunology*; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D008810:Mice, Inbred C57BL; D000071317:Nanog Homeobox Protein; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000201:enzymology / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D018874:Spheroids, Cellular; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology*; D059016:Tumor Microenvironment; D015854:Up-Regulation; D014611:Vaccination
D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase