Delivery of dendritic cells engineered to secrete IFN-α into central nervous system tumors enhances the efficacy of peripheral tumor cell vaccines:: Dependence on apoptotic pathways
Delivery of dendritic cells engineered to secrete IFN-α into central nervous system tumors enhances the efficacy of peripheral tumor cell vaccines:: Dependence on apoptotic pathways
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DOI：
10.4049/jimmunol.175.4.2730
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发表时间：
2005-08-15
影响因子：
4.4
通讯作者：
Okada, H
中科院分区：
文献类型：
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作者：
Kuwashima, N;Nishimura, F;Okada, H
我们测试了干扰素-α转导的树突状细胞(DC：DC-干扰素-α)对中枢神经系统肿瘤微环境的调节是否会增强细胞因子基因转导的肿瘤细胞外周疫苗的治疗效果。对荷GL261脑胶质瘤或MCA205肉瘤的小鼠，分别用相应的照射后的肿瘤细胞进行外周免疫，同时瘤内注射DC-干扰素-α。该方案延长了动物的存活时间，并诱导了表达TRAIL的肿瘤特异性CTL，TRAIL与穿孔素和Fas配体(FasL)协同参与了这些细胞的肿瘤特异性CTL活性。与这种方法相关的体内抗肿瘤活性可通过注射中和抗TRAIL或FasL的单抗而被取消，并且在穿孔素(-/-)、干扰素-γ(-/-)或FasL(-/-)小鼠中未观察到。转导抗凋亡蛋白细胞翻转基因的肿瘤细胞在体外对TRAIL或FasL介导的细胞凋亡和CTL杀伤活性具有抵抗作用。此外，联合治疗方案在颅内细胞倒置转导的MCA205脑瘤模型中无效。这些结果提示，DC-干扰素-α瘤内注射联合细胞因子基因转导的肿瘤细胞外周免疫治疗对凋亡信号通路敏感的脑肿瘤可能是一种有效的治疗方法。
We tested whether modulation of the CNS-tumor microenvironment by delivery of IFN-alpha-transduced dendritic cells (DCs: DC-IFN-alpha) would enhance the therapeutic efficacy of peripheral vaccinations with cytokine-gene transduced tumor cells. Mice bearing intracranial GL261 glioma or MCA205 sarcoma received peripheral immunizations with corresponding irradiated tumor cells engineered to express IL-4 or GM-CSFs, respectively, as well as intratumoral delivery of DC-IFN-a. This regimen prolonged survival of the animals and induced tumor-specific CTLs that expressed TRAIL, which in concert with perforin and Fas ligand (FasL) was involved in the tumor-specific CTL activity of these cells. The in vivo antitumor activity associated with this approach was abrogated by administration of neutralizing mAbs against TRAIL or FasL and was not observed in perforin(-/-), IFN-gamma(-/-), or FasL(-/-) mice. Transduction of the tumor cells with antiapoptotic protein cellular FLIP rendered the gene-modified cells resistant to TRAIL- or FasL-mediated apoptosis and to CTL killing activity in vitro. Furthermore, the combination therapeutic regimen was ineffective in an intracranial cellular FLIP-transduced MCA205 brain tumor model. These results suggest that the combination of intratumoral delivery of DC-IFN-alpha and peripheral immunization with cytokine-gene transduced tumor cells may be an effective therapy for brain tumors that are sensitive to apoptotic signaling pathways.