Established human papillomavirus type 16-expressing tumors are effectively eradicated following vaccination with long peptides
Established human papillomavirus type 16-expressing tumors are effectively eradicated following vaccination with long peptides
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DOI：
10.4049/jimmunol.169.1.350
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发表时间：
2002-07-01
影响因子：
4.4
通讯作者：
Melief, CJM
中科院分区：
文献类型：
--
作者：
Zwaveling, S;Mota, SCF;Melief, CJM
以多肽为基础的疫苗旨在诱导针对已建立的癌症的有效T细胞反应，到目前为止只取得了有限的临床成功，显然需要改进。在人类乳头状瘤病毒(HPV)16诱导的宫颈癌的临床前模型中，我们发现，与仅使用最小CTL表位的疫苗相比，HPV16衍生的35个氨基酸的长肽E7(43-77)(包含CTL表位和Th表位)诱导的E7特异性CD8(+)T细胞反应要强得多。我们证明了两种不同的机制对这种影响负责。首先，接种长肽可以产生E7特异性的CD4(+)Th细胞。诱导的E7特异性CD8(+)T细胞反应的水平被证明依赖于这些Th细胞与专业APC的相互作用。其次，我们证明，即使排除了T细胞的帮助，接种长肽和树突状细胞激活剂也能更好地诱导E7特异性CD8(+)T细胞。这表明，由于其大小，长肽最好是由专业的APC内吞、加工和呈递。此外，这种优越的HPV特异性T细胞诱导在治疗性初始增强疫苗中得到了证明，在这种疫苗中，长肽与树突状细胞激活的寡脱氧核苷酸-CpG混合在一起，导致了大的、已建立的HPV16表达的肿瘤的根除。由于这项研究中使用的疫苗类型在良好的生产实践条件下很容易制备，并且对人类是安全的，这些数据为未来的临床试验提供了重要信息。
Peptide-based vaccines aimed at the induction of effective T cell responses against established cancers have so far only met with limited clinical success and clearly need to be improved. In a preclinical model of human papillornavirus (HPV)16-induced cervical cancer we show that prime-boost vaccinations with the HPV16-derived 35 amino-acid long peptide E7(43-77), containing both a CTL epitope and a Th epitope, resulted in the induction of far more robust E7-specific CD8(+) T cell responses than vaccinations with the minimal CTL epitope only. We demonstrate that two distinct mechanisms are responsible for this effect. First, vaccinations with the long peptide lead to the generation of E7-specitic CD4(+) Th cells. The level of the induced E7-specific CD8(+) T cell response proved to be dependent on the interactions of these Th cells with professional APC. Second, we demonstrate that vaccination with the long peptide and dendritic cell-activating agents resulted in a superior induction of E7-specific CD8(+) T cells, even when T cell help was excluded. This suggests that, due to its size, the long peptide was preferably endocytosed, processed, and presented by professional APCs. Moreover, the efficacy of this superior HPV-specific T cell induction was demonstrated in therapeutic prime-boost vaccinations in which the long peptide admixed with the dendritic cell-activating adjuvant oligodeoxynucleotide-CpG resulted in the eradication of large, established HPV16-expressing tumors. Because the vaccine types used in this study are easy to prepare under good manufacturing practice conditions and are safe to administer to humans, these data provide important information for future clinical trials.