Modification of anti-tumor immunity by tolerogenic dendritic cells

Immunosuppressive functions of glucocorticoids (GC) can be mediated via various mechanisms, including the modulation of dendritic cells (DC). Our study investigates the effects of tolerogenic GC-treated DCs on NK and T cell anti-tumor responses in OT-1/Rag^−/− mice, expressing a transgenic TCR in CD8⁺ T cells. The effects caused by GC-treated DCs were compared to the responses to immunogenic, CpG-activated DCs. The effects of DCs on anti-tumor immune responses were analyzed using the EG7 tumor model, where the tumor cells express the peptide epitope recognized by OT-1 T cells. We observed that immunization with CpG and peptide-treated DCs protected against tumor growth by activation of NK cell response. Also, immunogenic DCs induced the expansion of cytotoxic CD8⁺OT-1 cells, expressing activation markers CD44 and CD69 and producing IFNγ. In contrast, the peptide and GC-treated DCs in OT-1 mice increased the numbers of immature Mac-1⁺CD27⁻ NK cells as well as Foxp3⁺ and IL-10 secreting CD8⁺OT-1 cells with suppressive properties. We conclude that the generation of tolerogenic DCs is one of many immunosuppressive mechanisms that can be induced by GC. Our study demonstrated that tolerogenic DCs modify anti-tumor immune response by suppressing NK cell activity and stimulating the formation of IL-10-secreting CD8⁺ Tregs.

糖皮质激素（glucocorticoids, GC）的免疫抑制功能可通过多种机制介导，其中包括对树突状细胞（dendritic cells, DC）的调控。本研究探讨了经致耐受性糖皮质激素处理的树突状细胞，对表达转基因T细胞受体（transgenic TCR）的CD8阳性T细胞的OT-1/Rag^−/−小鼠体内自然杀伤细胞（natural killer cells, NK）与T细胞抗肿瘤应答的影响。本研究将糖皮质激素处理的树突状细胞所引发的效应，与免疫原性CpG激活的树突状细胞所诱导的应答进行了对比。本研究采用EG7肿瘤模型分析树突状细胞对抗肿瘤免疫应答的影响，该模型中的肿瘤细胞表达可被OT-1 T细胞识别的肽表位。研究观察到，以CpG与肽段处理的树突状细胞进行免疫，可通过激活NK细胞应答抑制肿瘤生长。此外，免疫原性树突状细胞可诱导细胞毒性CD8阳性OT-1 T细胞扩增，这些细胞表达活化标记物CD44与CD69，并分泌干扰素γ（interferon γ, IFNγ）。与之相反，在OT-1小鼠中，经肽段与糖皮质激素处理的树突状细胞会增加未成熟Mac-1⁺CD27⁻ NK细胞的数量，同时增加Foxp3阳性以及分泌白细胞介素10（interleukin 10, IL-10）的具有免疫抑制功能的CD8阳性OT-1 T细胞的数量。本研究结论认为，致耐受性树突状细胞的生成是糖皮质激素可诱导的多种免疫抑制机制之一。本研究证实，致耐受性树突状细胞可通过抑制NK细胞活性、促进分泌IL-10的CD8阳性调节性T细胞（regulatory T cells, Tregs）的形成，来改变抗肿瘤免疫应答。