Nakamura Masaki, Iwahashi Makoto, Nakamori Mikihito, Ueda Kentaro, Ojima Toshiyasu, Naka Teiji, Ishida Koichiro, Yamaue Hiroki
Second Department of Surgery, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama, Japan.
Oncology. 2005;68(2-3):163-70. doi: 10.1159/000086770. Epub 2005 Jul 4.
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.
多项研究表明，使用负载特定肿瘤抗原肽的树突状细胞（DCs）进行疫苗治疗可有效诱导抗肿瘤免疫。据报道，肽负载的DC治疗对黑色素瘤有效，但对胃肠道恶性肿瘤等上皮实体瘤的抗肿瘤治疗效果仍不充分。最近，有报道称，使用转导替代肿瘤抗原基因的DCs进行疫苗治疗可引发强大的治疗性抗肿瘤免疫。在本研究中，我们比较了使用转导天然肿瘤抗原的DCs与肽负载的DCs进行疫苗治疗的效果。从小鼠骨髓中分离的DCs通过腺病毒转导鼠内源性肿瘤抗原gp70基因（该基因在CT26细胞中表达），或者用源自gp70的免疫显性肽AH-1负载DCs。我们在诱导抗原特异性细胞毒性T淋巴细胞（CTL）反应、针对肿瘤细胞的CD4 + T细胞反应、DCs的迁移能力以及体内治疗性免疫方面比较了这两种癌症疫苗。在用gp70基因转导的DCs免疫的小鼠中，脾细胞对用AH-1负载的CT26和Meth-A的细胞毒性活性高于用AH-1负载的DCs免疫的小鼠。用gp70基因转导的DCs免疫的小鼠诱导产生的CD4 + T细胞在用CT26刺激后产生的IFN-γ水平高于用AH-1负载的DCs免疫的小鼠（p < 0.0001），提示转导肿瘤相关抗原（TAA）基因的DCs诱导了肿瘤特异性CD4 + T细胞，并且这些CD4 + T细胞在CD8 + T细胞反应的启动阶段对诱导CD8 + CTL起关键作用。此外，用TAA基因腺病毒转导的DCs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gp70基因转导的DCs进行疫苗接种比使用AH-1负载的DCs提供了显著更高的治疗效果。这些结果表明，使用腺病毒转导TAA基因的DCs进行疫苗治疗可引发强大的抗肿瘤免疫，可能对临床应用有用。
