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 stemnessassociated 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 tyrosinaserelated 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-b1 production. Additionally, Nanog regulated TGF-b1 under hypoxia by directly binding the TGF-b1 proximal promoter. Collectively, our data establish a novel functional link between hypoxia-induced Nanog and TGF-b1 regulation and point to a major role of Nanog in hypoxia-driven immunosuppression. The Journal of Immunology, 2013, 191: 000–000.