Persistent human papillomavirus (HPV) infection is responsible for practically all cervical and a high proportion of anogenital and oropharyngeal cancers. Therapeutic HPV vaccines in clinical development show great promise in improving outcomes for patients who mount an anti-HPV T-cell response; however, far from all patients elicit a sufficient immunological response. This demonstrates a translational gap between animal models and human patients. Here, we investigated the potential of a new assay consisting of co-culturing vaccine-transduced dendritic cells (DCs) with syngeneic, healthy, human peripheral blood mononuclear cells (PBMCs) to mimic a human in vivo immunization. This new promising human ex vivo PBMC assay was evaluated using an innovative therapeutic adenovirus (Adv)-based HPV vaccine encoding the E1, E2, E6, and E7 HPV16 genes. This new method allowed us to show that vaccine-transduced DCs yielded functional effector T cells and unveiled information on immunohierarchy, showing E1-specific T-cell immunodominance over time. We suggest that this assay can be a valuable translational tool to complement the known animal models, not only for HPV therapeutic vaccines, and supports the use of E1 as an immunotherapeutic target. Nevertheless, the findings reported here need to be validated in a larger number of donors and preferably in patient samples.
持续性人乳头瘤病毒（HPV）感染是几乎所有宫颈癌以及大部分肛门生殖器和口咽部癌症的致病原因。目前处于临床研发阶段的治疗性HPV疫苗在提升能够产生抗HPV T细胞应答的患者预后方面展现出巨大潜力，然而并非所有患者都能引发足够的免疫应答。这揭示了动物模型与人类患者之间存在转化研究鸿沟。本研究探讨了一种新型检测方法的潜力：通过将疫苗转导的树突状细胞（DCs）与同源健康人外周血单个核细胞（PBMCs）共培养，模拟人体内免疫接种过程。我们采用一种编码HPV16 E1、E2、E6和E7基因的创新性腺病毒载体治疗性HPV疫苗，对这一前景广阔的新型人源离体PBMC检测法进行了评估。该方法成功证明疫苗转导的DCs能够产生功能性效应T细胞，并揭示了免疫层级特征——随时间推移呈现E1特异性T细胞的免疫显性优势。我们认为该检测法可作为重要的转化研究工具，不仅适用于HPV治疗性疫苗研发，还能补充现有动物模型的不足，同时为将E1作为免疫治疗靶点提供了依据。但需要指出的是，本研究结果尚需在更多供体样本中验证，并最好在患者样本中得到进一步证实。
肿瘤(癌症)患者之家