A novel "priming-boosting" strategy for immune interventions in cervical cancer
A novel "priming-boosting" strategy for immune interventions in cervical cancer
复制标题
宫颈癌免疫干预的新型“启动-增强”策略。
DOI：
10.1016/j.molimm.2014.12.007
复制
发表时间：
2015
影响因子：
3.6
通讯作者：
Ma Ding
中科院分区：
文献类型：
--
作者：
Liao Shujie;Zhang Weina;Hu Xiaoji;Wang Wei;Deng Dongrui;Wang Hui;Wang Changyu;Zhou Jianfeng;Wang Shixuan;Zhang Hanwang;Ma Ding
尽管人乳头瘤病毒（HPV）预防性疫苗的发展令人鼓舞，但它不能改善持续的感染。因此，迫切需要一种新的疫苗，可以预防和治疗宫颈癌，并治愈癌前病变。在这项研究中，我们构建了两种基于肽的疫苗。第一种是同时靶向HPV 16上的三个关键致癌表位（E5-E6-E7）的短期长肽（ST-LP）疫苗。我们在感染了与HPV 16 E5 DNA融合的重组腺相关病毒（rAAV）的小鼠TC-1细胞（rTC-1细胞）中测试了这种疫苗，该细胞作为细胞模型;我们还在装有rTC-1细胞的免疫活性小鼠中测试了这种疫苗，该细胞作为异位肿瘤模型。ST-LP注射产生了强大的细胞介导的免疫力，能够攻击和消除异常的抗原携带细胞。此外，为了延长免疫原性能力，我们设计了一种独特的rAAV，其编码第二种长期长肽（LT-LP）疫苗的三个预测表位。此外，我们使用了连续再注射的新免疫策略，其中以一周的间隔（第0、7、14天）进行三次ST-LP注射，然后在第120天进行一次LT-LP注射。我们的体外和体内研究表明，这种策略可以增强免疫反应，对靶细胞产生更长时间和更强的保护作用，并且小鼠完全免受肿瘤生长的影响。我们的研究结果表明，用ST-LP疫苗引发免疫系统，然后用LT-LP疫苗加强免疫系统可以产生对HPV 16阳性肿瘤的快速、稳健、持久的细胞毒性T淋巴细胞应答。
Despite the encouraging development of a preventive vaccine for human papillomavirus (HPV), it cannot improve ongoing infections. Therefore, a new vaccine is urgently needed that can prevent and treat cervical cancer, and cure pre-cancerous lesions. In this study, we constructed two peptide-based vaccines. The first was a short-term, long-peptide (ST-LP) vaccine that simultaneously targeted three key carcinogenic epitopes (E5–E6–E7) on HPV16. We tested this vaccine in murine TC-1 cells infected with a recombinant adeno-associated virus (rAAV) fused with HPV16E5 DNA (rTC-1 cells), which served as a cell model; we also tested it in immune-competent mice loaded with rTC-1 cells, which served as an ectopic tumor model. The ST-LP injections resulted in strong, cell-mediated immunity, capable of attacking and eliminating abnormal antigen-bearing cells. Furthermore, to prolong immunogenic capability, we designed a unique rAAV that encoded the three predicted epitopes for a second, long-term, long-peptide (LT-LP) vaccine. Moreover, we used a new immune strategy of continuous re-injections, where three ST-LP injections were performed at one-week intervals (days 0, 7, 14), then one LT-LP injection was performed on day 120. Our in vitro and in vivo studies revealed that this strategy could boost the immune response to produce longer and stronger protection against target cells, and mice were thoroughly protected from tumor growth. Our results showed that priming the immune system with the ST-LP vaccine, followed by boosting the immune system with the LT-LP vaccine could generate a rapid, robust, durable cytotoxic T-lymphocyte response to HPV16-positive tumors.