Tumor Immunology, Children's Cancer Research Institute, St. Anna Kinderkrebsforschung e.V., Zimmermannplatz 10, Vienna, Austria.
Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innrain 80, Innsbruck, Austria.
Cell Immunol. 2018 Mar;325:33-40. doi: 10.1016/j.cellimm.2018.01.014. Epub 2018 Feb 2.
Gangliosides shed by tumors into their microenvironment (TME) are immunoinhibitory. Interferon-γ (IFN-γ) may boost antitumor immune responses. Thus we wondered whether IFN-γ would counteract tumor ganglioside-mediated immune suppression. To test this hypothesis, we exposed human monocyte-derived LPS-activated dendritic cells (DC) to IFN-γ and to a highly purified ganglioside, GD1a. DC ganglioside exposure decreased TLR-dependent p38 signaling, explaining the previously observed ganglioside-induced down-modulation of pro-inflammatory surface markers and cytokines. Strikingly, while increasing LPS-dependent DC responses, IFN-γ unexpectedly did not counteract the inhibitory effects of GD1a. Rather, induction of indoleamine 2,3-dioxygenase (IDO1), and expression of STAT1/IRF-1 and programmed cell death ligand (PD-L1), indicated that the immunoinhibitory, not an immune stimulatory, IFN-γ-signaling axis, was active. The combination, IFN-γ and DC ganglioside enrichment, markedly impaired DC stimulatory potential of CD8 T-cells. We suggest that gangliosides and IFN-γ may act in concert as immunosuppressive mediators in the TME, possibly promoting tumor progression.
肿瘤排入其微环境（TME）中的神经节苷脂具有免疫抑制作用。干扰素-γ（IFN-γ）可能会增强抗肿瘤免疫反应。因此，我们想知道 IFN-γ 是否会抵消肿瘤神经节苷脂介导的免疫抑制。为了验证这一假设，我们将人单核细胞衍生的脂多糖激活的树突状细胞（DC）暴露于 IFN-γ和高度纯化的神经节苷脂 GD1a 中。DC 神经节苷脂暴露降低了 TLR 依赖性 p38 信号传导，解释了先前观察到的神经节苷脂诱导的促炎表面标志物和细胞因子下调。令人惊讶的是，IFN-γ 虽然增加了 LPS 依赖性 DC 反应，但并没有抵消 GD1a 的抑制作用。相反，诱导吲哚胺 2,3-双加氧酶（IDO1）的表达以及 STAT1/IRF-1 和程序性细胞死亡配体（PD-L1）的表达表明，免疫抑制而不是免疫刺激的 IFN-γ 信号通路是活跃的。IFN-γ 和 DC 神经节苷脂富集的联合作用显著损害了 CD8 T 细胞的 DC 刺激潜能。我们认为，神经节苷脂和 IFN-γ 可能在 TME 中协同作用作为免疫抑制介质，可能促进肿瘤进展。
