Intra-tumoral dendritic cells increase efficacy of peripheral vaccination by modulation of glioma microenvironment
Intra-tumoral dendritic cells increase efficacy of peripheral vaccination by modulation of glioma microenvironment
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DOI：
10.1093/neuonc/nop024
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发表时间：
2010-04-01
期刊：
影响因子：
15.9
通讯作者：
Finocchiaro, Gaetano
中科院分区：
文献类型：
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作者：
Pellegatta, Serena;Poliani, Pietro Luigi;Finocchiaro, Gaetano
试验数据显示，通过皮下（SC）递送树突状细胞（DC）进行瘤内（IT）注射可延长多形性胶质母细胞瘤（GBM）患者的生存期。使用类似于 GBM 的小鼠模型，我们研究了这种效应背后的免疫机制。 C57BL6/N 小鼠接受脑部注射 GL261 神经胶质瘤细胞。 7天后，对小鼠进行3次SC注射DC，同时进行或不进行1次IT注射DC。由 GL261 裂解物脉冲诱导的 DC 成熟对于产生有效的免疫反应是必要的。 IT 注射脉冲 (pDC) 而不是非脉冲 DC (uDC)，无论是其本身还是与 SC-pDC 组合，均显着增加了存活率（与对照相比，P < .001）。接受 IT-pDC 加 SC-pDC 治疗的小鼠比仅接受 SC-pDC 治疗的小鼠存活时间更长 (P = .03)。在肿瘤实质中可检测到注射的pDC，但在颈部淋巴结中未检测到。在注射 IT-pDC 的神经胶质瘤中，与其他组相比，CD8+ 细胞的数量明显增多，而 Foxp3+ 细胞的数量明显减少。使用实时聚合酶链反应，我们还发现用 SC-pDC 和 IT-pDC 治疗的小鼠中 IFN-γ 和 TNF-α 的表达增强，转化生长因子-β (TGF-β) 和 Foxp3 的表达降低。在体外，pDC 比 uDC 产生更多的 TNF-α：在培养基中添加 TNF-α 会降低神经胶质瘤细胞的增殖。总体而言，结果表明，IT-pDC 通过肿瘤微环境中细胞因子的促免疫调节、Treg 细胞的减少以及 TNF-α 直接抑制肿瘤增殖来增强 SC-pDC 引发的抗肿瘤免疫反应。
Pilot data showed that adding intratumoral (IT) injection of dendritic cells (DCs) prolongs survival of patients affected by glioblastoma multiforme (GBM) treated by subcutaneous (SC) delivery of DCs. Using a murine model resembling GBM, we investigated the immunological mechanisms underlying this effect. C57BL6/N mice received brain injections of GL261 glioma cells. Seven days later, mice were treated by 3 SC injections of DCs with or without 1 IT injection of DCs. DC maturation, induced by pulsing with GL261 lysates, was necessary to develop effective immune responses. IT injection of pulsed (pDC), but not unpulsed DCs (uDC), increased significantly the survival, either per se or in combination with SC-pDC (P < .001 vs controls). Mice treated by IT-pDC plus SC-pDC survived longer than mice treated by SC-pDC only (P = .03). Injected pDC were detectable in tumor parenchyma, but not in cervical lymph nodes. In gliomas injected with IT-pDC, CD8+ cells were significantly more abundant and Foxp3+ cells were significantly less abundant than in other groups. Using real-time polymerase chain reaction, we also found enhanced expression of IFN-gamma and TNF-alpha and decreased expression of transforming growth factor-beta (TGF-beta) and Foxp3 in mice treated with SC-pDC and IT-pDC. In vitro, pDC produced more TNF-alpha than uDC: addition of TNF-alpha to the medium decreased the proliferation of glioma cells. Overall, the results suggest that IT-pDC potentiates the anti-tumor immune response elicited by SC-pDC by pro-immune modulation of cytokines in the tumor microenvironment, decrease of Treg cells, and direct inhibition of tumor proliferation by TNF-alpha.