Dendritic cells transduced with tumor-associated antigen gene elicit potent therapeutic antitumor immunity: Comparison with immunodominant peptide-pulsed DCs
Dendritic cells transduced with tumor-associated antigen gene elicit potent therapeutic antitumor immunity: Comparison with immunodominant peptide-pulsed DCs
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DOI：
10.1159/000086770
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发表时间：
2005-01-01
期刊：
影响因子：
3.5
通讯作者：
Yamaue, H
中科院分区：
文献类型：
--
作者：
Nakamura, M;Iwahashi, M;Yamaue, H
一些研究表明，使用负载特异性肿瘤抗原肽的树突状细胞（DCs）的疫苗治疗可以有效地诱导抗肿瘤免疫。据报道，肽脉冲DC疗法对黑色素瘤是有效的，但它仍然不足以显示对上皮实体瘤如胃肠道恶性肿瘤的抗肿瘤治疗效果。最近，有报道使用转导有替代肿瘤抗原基因的DC的疫苗治疗可以引发有效的治疗性抗肿瘤免疫。在这项研究中，我们研究了疫苗治疗的效果，使用天然肿瘤抗原转导的DC与肽脉冲的DC相比。用在CT 26细胞中表达的鼠内源性肿瘤抗原gp 70基因腺病毒转导来自鼠骨髓的DC，或者用来自gp 70的免疫显性肽AH-1脉冲DC。我们比较了这两种癌症疫苗在诱导抗原特异性细胞毒性T淋巴细胞（CTL）反应，CD 4 + T细胞对肿瘤细胞的反应，DC的迁移能力和治疗性免疫在体内。gp 70基因转导的DC免疫小鼠脾细胞对AH-1致敏的CT 26和Meth-A的杀伤活性高于AH-1致敏的DC。gp 70基因转导的DC免疫小鼠诱导的CD 4 + T细胞在CT 26刺激下产生的IFN-γ水平高于AH-1脉冲的DC免疫小鼠（p < 0.0001），并且表明用肿瘤相关抗原（TAA）基因转导的DC诱导肿瘤特异性CD 4 + T细胞，这些CD 4 + T细胞在诱导CD 8 + CTL的CD 8 + T细胞应答的启动阶段起关键作用。此外，TAA基因转染的DC显示CC趋化因子受体7的表达增强，并提高了向引流淋巴结的迁移能力。在皮下模型中，使用gp 70基因转导的DC的疫苗接种提供了显着高于使用AH-1脉冲的DC的治疗效果。结果表明，腺病毒介导的TAA基因转染的DC疫苗能诱导机体产生较强的抗肿瘤免疫力，具有临床应用价值。版权所有（C）2005 S. Karger AG，巴塞尔。
Several studies have shown that vaccine therapy using dendritic cells (DCs) pulsed with specific tumor antigen peptides can effectively induce antitumor immunity. Peptide-pulsed DC therapy is reported to be effective against melanoma, while it is still not sufficient to show the antitumor therapeutic effect against epithelial solid tumors such as gastrointestinal malignancies. Recently, it has been reported that vaccine therapy using DCs transduced with a surrogate tumor antigen gene can elicit a potent therapeutic antitumor immunity. In this study, we investigated the efficacy of vaccine therapy using DCs transduced with the natural tumor antigen in comparison with peptide-pulsed DCs. DCs derived from murine bone marrow were adenovirally transduced with murine endogenous tumor antigen gp70 gene, which is expressed in CT26 cells, or DCs were pulsed with the immunodominant peptide AH-1 derived from gp70. We compared these two cancer vaccines in terms of induction of antigen-specific cytotoxic T lymphocyte (CTL) responses, CD4+ T cell response against tumor cells, migratory capacity of DCs and therapeutic immunity in vivo. The cytotoxic activity of splenocytes against CT26 and Meth-A pulsed with AH-1 in mice immunized with gp70 gene-transduced DCs was higher than that with AH-1-pulsed DCs. CD4+ T cells induced from mice immunized with gp70 gene-transduced DCs produced higher levels of IFN-gamma by stimulation with CT26 than those from mice immunized with AH-1-pulsed DCs (p < 0.0001), and it was suggested that DCs transduced with tumor-associated antigen (TAA) gene induced tumor-specific CD4+ T cells, and those CD4+ T cells played a critical role in the priming phase of the CD8+ T cell response for the induction of CD8+ CTL. Furthermore, DCs adenovirally transduced with TAA gene showed an enhancement of expression of CC chemokine receptor 7 and improved the migratory capacity to draining lymph nodes. In subcutaneous models, the vaccination using gp70 gene-transduced DCs provided a remarkably higher therapeutic efficacy than that using AH-1-pulsed DCs. These results suggested that vaccine therapy using DCs adenovirally transduced with TAA gene can elicit potent antitumor immunity, and may be useful for clinical application. Copyright (C) 2005 S. Karger AG, Basel.