Zhang Shuren, Zhang Youhui
Peking Union Medical College, Department of Immunology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing 100021, China.
Future Oncol. 2008 Apr;4(2):299-303. doi: 10.2217/14796694.4.2.299.
Dendritic cells play a pivotal role in immune induction. Dendritic cells perform antigen uptake, processing and presentation to T cells only when they are matured and in the functional state. In the development of a vaccine, it is of utmost importance to consider how to make dendritic cells' functions immunologically adequate. In this paper, we report the development of a series of antitumor DNA vaccines with similar structural framework, in which a gene encoding tumor-associated antigenic peptide is ligated upstream to the gene coding secondary lymphoid-tissue chemokine and downstream to the gene encoding the Fc portion of IgG (named chemotactic-antigen DNA vaccine [CADV]). CCR7(+) T, B, natural killer and dendritic cells can be attracted by secondary lymphoid-tissue chemokine, and Fc facilitates antigen uptake via Fc receptors expressed on dendritic cells. In a series of experiments in mice vaccinated by CADV with such tumor-associated antigenic specificities as HPV-16 E7, PSA-PSM-PAP, HER-2/neu, p53 and hTERT, CADV can attract immune cells to the vaccine inoculation site, remarkably inhibit tumor growth and extend survival time in tumor-bearing mice. The antitumor effect is more efficacious than that in mice treated with SLC-Ag or Ag-Fc hybrid gene. Tumor-associated antigenic-specific cytotoxic T lymphocytes can be induced by in vitro experiment in a human system. When combined with measures blocking the negative immune feedback circuits, the therapeutic effect of the vaccine can be further enhanced. Large-scale production of CADV is possible for clinical application.
树突状细胞在免疫诱导中起关键作用。树突状细胞只有在成熟并处于功能状态时才会摄取、处理抗原并将其呈递给T细胞。在疫苗研发过程中，考虑如何使树突状细胞的功能在免疫学上达到足够水平至关重要。在本文中，我们报告了一系列具有相似结构框架的抗肿瘤DNA疫苗的研发情况，其中编码肿瘤相关抗原肽的基因连接在编码二级淋巴组织趋化因子的基因上游，编码IgG Fc部分的基因下游（称为趋化性抗原DNA疫苗[CADV]）。二级淋巴组织趋化因子可吸引CCR7(+) T细胞、B细胞、自然杀伤细胞和树突状细胞，Fc则通过树突状细胞上表达的Fc受体促进抗原摄取。在一系列针对接种了具有HPV-16 E7、PSA-PSM-PAP、HER-2/neu、p53和hTERT等肿瘤相关抗原特异性的CADV的小鼠实验中，CADV可将免疫细胞吸引至疫苗接种部位，显著抑制荷瘤小鼠的肿瘤生长并延长其存活时间。其抗肿瘤效果比用SLC-Ag或Ag-Fc杂交基因处理的小鼠更有效。在人体系统中通过体外实验可诱导肿瘤相关抗原特异性细胞毒性T淋巴细胞。当与阻断负性免疫反馈回路的措施相结合时，疫苗的治疗效果可进一步增强。CADV有可能大规模生产用于临床应用。
