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Therapeutic vaccination using minimal HPV16 epitopes in a novel MHC-humanized murine HPV tumor model.
OncoImmunology ( IF 6.5 ) Pub Date : 2018-12-14 , DOI: 10.1080/2162402x.2018.1524694
Sebastian Kruse 1, 2 , Marleen Büchler 1, 2 , Philipp Uhl 2, 3 , Max Sauter 2, 3 , Philipp Scherer 1 , Tammy C T Lan 1 , Samantha Zottnick 1, 2 , Alexandra Klevenz 1 , Ruwen Yang 2, 4 , Frank Rösl 4 , Walter Mier 3 , Angelika B Riemer 1, 5
Affiliation  

Therapeutic vaccination as a treatment option for HPV-induced cancers is actively pursued because the two HPV proteins E6 and E7 represent ideal targets for immunotherapy, as they are non-self and expressed in all tumor stages. MHC-humanized mice are valuable tools for the study of therapeutic cancer vaccines - given the availability of a suitable tumor model. Here, we present for the first time an HPV16 tumor model suitable for fully MHC-humanized A2.DR1 mice, PAP-A2 cells, which in contrast to existing HPV16 tumor models allows the exclusive study of HLA-A2- and DR1-mediated immune responses, without any interfering murine MHC-presented epitopes. We used several HPV16 epitopes that were shown to be presented on human cervical cancer cells by mass spectrometry for therapeutic anti-tumor vaccination in the new tumor model. All epitopes were immunogenic when rendered amphiphilic by incorporation into a molecule containing stearic acids. Prophylactic and therapeutic vaccination experiments with the epitope E7/11-19 demonstrated that effective immune responses could be induced with these vaccination approaches in A2.DR1 mice. Interestingly, the combination of E7/11-19 with other immunogenic HPV16 E6/E7 epitopes caused a reduction of vaccine efficacy, although all tested combinations resulted in a survival benefit. In summary, we present the first HPV16 tumor model for exclusive studies of HLA-A2-mediated anti-HPV tumor immune responses and show anti-tumor efficacy of minimal epitope vaccines.

中文翻译:

在新型MHC人源化鼠类HPV肿瘤模型中,使用最少的HPV16表位进行治疗性疫苗接种。

由于两种HPV蛋白E6和E7都是非自身的并且在所有肿瘤阶段均表达,因此积极寻求将治疗性疫苗接种作为HPV诱导的癌症的治疗选择。考虑到合适的肿瘤模型的可用性,MHC人源化小鼠是治疗癌症疫苗的有价值的工具。在这里,我们首次提出适用于完全MHC人源化A2.DR1小鼠的PAP-A2细胞的HPV16肿瘤模型,与现有的HPV16肿瘤模型相比,它可以专门研究HLA-A2-和DR1介导的免疫反应,没有任何干扰的小鼠MHC呈现的表位。我们使用了几种HPV16表位,这些表位已通过质谱显示在人宫颈癌细胞上,用于在新的肿瘤模型中进行治疗性抗肿瘤疫苗接种。当通过掺入含有硬脂酸的分子而成为两亲性时,所有表位都是免疫原性的。用表位E7 / 11-19进行的预防性和治疗性疫苗接种实验表明,用这些疫苗接种方法可以在A2.DR1小鼠中诱导有效的免疫应答。有趣的是,E7 / 11-19与其他免疫原性HPV16 E6 / E7表位的组合导致疫苗效力降低,尽管所有测试的组合均带来了生存益处。总之,我们提出了第一个HPV16肿瘤模型,用于独家研究HLA-A2介导的抗HPV肿瘤免疫反应,并显示了最小表位疫苗的抗肿瘤功效。用表位E7 / 11-19进行的预防性和治疗性疫苗接种实验表明,用这些疫苗接种方法可以在A2.DR1小鼠中诱导有效的免疫应答。有趣的是,E7 / 11-19与其他免疫原性HPV16 E6 / E7表位的组合导致疫苗效力降低,尽管所有测试的组合均带来了生存益处。总之,我们提出了第一个HPV16肿瘤模型,用于独家研究HLA-A2介导的抗HPV肿瘤免疫反应,并显示了最小表位疫苗的抗肿瘤功效。用表位E7 / 11-19进行的预防性和治疗性疫苗接种实验表明,用这些疫苗接种方法可以在A2.DR1小鼠中诱导有效的免疫应答。有趣的是,E7 / 11-19与其他免疫原性HPV16 E6 / E7表位的组合导致疫苗效力降低,尽管所有测试的组合均带来了生存益处。总之,我们提出了第一个HPV16肿瘤模型,用于独家研究HLA-A2介导的抗HPV肿瘤免疫反应,并显示了最小表位疫苗的抗肿瘤功效。
更新日期:2018-10-29
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