Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics
Plasmacytoid Dendritic Cells in the Tumor Microenvironment: Immune Targets for Glioma Therapeutics
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DOI：
10.1593/neo.12794
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发表时间：
2012-08-01
期刊：
影响因子：
4.8
通讯作者：
Castro, Maria G.
中科院分区：
文献类型：
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作者：
Candolfi, Marianela;King, Gwendalyn D.;Castro, Maria G.
腺病毒介导的免疫刺激细胞因子Flt3L和条条性细胞毒性胸苷激酶（TK）在临床前胶质瘤（多形性胶质母细胞瘤[GBM]）模型中诱导肿瘤消退和长期生存。Flt3L诱导浆细胞样树突状细胞（pDCs）向大脑扩张和募集。尽管pDCs可以呈递抗原并产生强大的炎性细胞因子，即干扰素a (ifn - α)，但它们在肿瘤免疫学中的作用仍存在争议。因此，我们研究了pDCs和ifn - α在Ad中的作用。TK / GCV +广告。flt3l介导的抗gbm治疗效果。我们的数据表明，联合基因治疗诱导浆细胞样dc （pDCs）募集到肿瘤肿块中；能够在体内吞噬、释放ifn - α和启动t细胞。因此，我们接下来使用pDCs或编码ifn - α的Ad载体在肿瘤微环境中传递。当大鼠用Ad。TK/GCV联合pDCs或ad - ifn - α，分别表现出35%和50%的生存率。然而，颅内给药Ad。TK/GCV + AdFlt3L具有较高的安全性，ad - ifn - α可导致严重的局部炎症，并伴有神经系统和全身不良反应。为了阐明免疫治疗的效果是否依赖于分泌ifn - α的pDCs，我们使用了编码IFNa拮抗剂B18R的Ad载体，该载体消除了Ad的抗肿瘤作用。TK/GCV + Ad.Flt3L。我们的数据表明，激活的pDCs释放ifn - α在Ad介导的抗肿瘤作用中起关键作用。TK/GCV + Ad.Flt3L。综上所述，我们的研究结果表明，pDCs通过产生ifn - α介导抗GBM的治疗效果，因此操纵pDCs构成了治疗GBM的一个有吸引力的新治疗靶点。
Adenovirus-mediated delivery of the immune-stimulatory cytokine Flt3L and the conditionally cytotoxic thymidine kinase (TK) induces tumor regression and long-term survival in preclinical glioma (glioblastoma multiforme [GBM]) models. Flt3L induces expansion and recruitment of plasmacytoid dendritic cells (pDCs) into the brain. Although pDCs can present antigen and produce powerful inflammatory cytokines, that is, interferon a (IFN-alpha), their role in tumor immunology remains debated. Thus, we studied the role of pDCs and IFN-alpha in Ad.TK/GCV+ Ad. Flt3L-mediated anti-GBM therapeutic efficacy. Our data indicate that the combined gene therapy induced recruitment of plasmacytoid DCs (pDCs) into the tumor mass; which were capable of in vivo phagocytosis, IFN-alpha release, and T-cell priming. Thus, we next used either pDCs or an Ad vector encoding IFN-alpha deliveredwithin the tumor microenvironment. When rats were treated with Ad.TK/GCV in combination with pDCs or Ad-IFN-alpha, they exhibited 35% and 50% survival, respectively. However, whereas intracranial administration of Ad. TK/GCV + Ad.Flt3L exhibited a high safety profile, Ad-IFN-alpha led to severe local inflammation, with neurologic and systemic adverse effects. To elucidate whether the efficacy of the immunotherapy was dependent on IFN-alpha-secreting pDCs, we administered an Ad vector encoding B18R, an IFNa antagonist, which abrogated the antitumoral effect of Ad.TK/GCV + Ad.Flt3L. Our data suggest that IFN-alpha release by activated pDCs plays a critical role in the antitumor effect mediated by Ad.TK/GCV + Ad.Flt3L. In summary, taken together, our results demonstrate that pDCs mediate anti-GBM therapeutic efficacy through the production of IFN-alpha, thus manipulation of pDCs constitutes an attractive new therapeutic target for the treatment of GBM.