INSERM Unité 753, Institut Gustave Roussy, 94800 Villejuif, France.
J Immunol. 2013 Dec 15;191(12):5802-6. doi: 10.4049/jimmunol.1302140. Epub 2013 Nov 13.
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.
新出现的证据表明肿瘤缺氧与免疫抑制之间存在关联。在这项研究中，我们研究了缺氧诱导的 Nanog（一种与干细胞特性相关的转录因子）在免疫抑制中的作用。我们观察到，缺氧诱导的 Nanog 与 B16-F10 细胞获得类似干细胞的特性相关。我们进一步表明，Nanog 选择性地在 B16-F10 肿瘤的缺氧区域中被诱导。稳定的短发夹 RNA 介导的 Nanog 耗竭，结合黑色素细胞分化 Ag 酪氨酸酶相关蛋白-2 肽疫苗接种，导致 B16-F10 肿瘤生长完全抑制。Nanog 靶向治疗通过调节 TGF-β1 的产生，显著减少了肿瘤床中的免疫抑制细胞（调节性 T 细胞和巨噬细胞），并增加了 CD8(+)T 效应细胞。此外，Nanog 通过直接结合 TGF-β1 近端启动子在缺氧条件下调节 TGF-β1。总之，我们的数据建立了缺氧诱导的 Nanog 与 TGF-β1 调节之间的新的功能联系，并指出 Nanog 在缺氧驱动的免疫抑制中起着重要作用。
