Therapeutic effect of α-galactosylceramide-loaded dendritic cells genetically engineered to express SLC/CCL21 along with tumor antigen against peritoneally disseminated tumor cells
Therapeutic effect of α-galactosylceramide-loaded dendritic cells genetically engineered to express SLC/CCL21 along with tumor antigen against peritoneally disseminated tumor cells
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DOI：
10.1111/j.1349-7006.2005.00123.x
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发表时间：
2005-12-01
期刊：
影响因子：
5.7
通讯作者：
Senju, S
中科院分区：
文献类型：
--
作者：
Matsuyoshi, H;Hirata, S;Senju, S
天然免疫和获得性免疫的密切配合对于诱导真正有效的抗肿瘤免疫是必不可少的。我们测试了一种增强NKT细胞和传统抗原特异性T细胞之间的相互作用的策略，使用装载αGalCer的树突状细胞，通过基因工程表达抗原和趋化因子，吸引传统T细胞和NKT细胞。利用小鼠ES细胞体外分化DC的方法，获得了表达模式抗原OVA的DC以及SLC/CCL21或由干扰素-γ/CXCL9诱导的单核细胞因子。将ES-DC负载α-GalCer，并转移到荷有OVA表达的黑色素瘤MO4的小鼠体内，评估其激发抗肿瘤免疫的能力。体内转移表达OVA的ES-DC，刺激OVA反应性T细胞，或负载α-GalCer的非转基因ES-DC，刺激NKT细胞，产生显著但有限的保护作用。散布的MO4。体内转移前，将α-GalCer负载到表达OVA的ES-DC上，可产生更强的抗肿瘤作用，而抗CD8、抗NK1.1或抗asialo GM1抗体的作用可被阻断。Alpha-GalCer负载表达SLC和OVA的ES-DC双转染体诱导的抗肿瘤免疫效果最强。因此，α-GalCer负载的表达肿瘤相关抗原的ES-DC与SLC一起可以刺激多个效应细胞亚群，从而对腹膜播散性肿瘤细胞产生强大的治疗作用。本研究提出了一种将α-GalCer用于免疫治疗腹膜播散性癌症的新方法。
The close cooperation of both innate and acquired immunity is essential for the induction of truly effective antitumor immunity. We tested a strategy to enhance the cross-talk between NKT cells and conventional antigen-specific T cells with the use of alpha GalCer-loaded dendritic cells genetically engineered to express antigen plus chemokine, attracting both conventional T cells and NKT cells. DC genetically engineered to express a model antigen, OVA, along with SLC/CCL21 or monokine induced by IFN-gamma/ CXCL9, had been generated using a method based on in vitro differentiation of DC from mouse ES cells. The ES-DC were loaded with alpha-GalCer and transferred to mice bearing MO4, an OVA-expressing melanoma, and their capacity to evoke antitumor immunity was evaluated. In vivo transfer of either OVA-expressing ES-DC, stimulating OVA-reactive T cells, or alpha-GalCer-loaded non-transfectant ES-DC, stimulating NKT cells, elicited a significant but limited degree of protection against the i.p. disseminated MO4. A more potent antitumor effect was observed when alpha-GalCer was loaded to ES-DC expressing OVA before in vivo transfer, and the effect was abrogated by the administration of anti-CD8, anti-NK1.1 or anti-asialo GM1 antibody. alpha-GalCer-loaded double transfectant ES-DC expressing SLC along with OVA induced the most potent antitumor immunity. Thus, alpha-GalCer-loaded ES-DC expressing tumor-associated antigen along with SLC can stimulate multiple subsets of effector cells to induce a potent therapeutic effect against peritoneally disseminated tumor cells. The present study suggests a novel way to use alpha-GalCer in immunotherapy for peritoneally disseminated cancer.