Tuong Z K, Noske K, Kuo P, Bashaw A A, Teoh S M, Frazer I H
The University of Queensland, Faculty of Medicine, Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia.
The University of Queensland, Faculty of Medicine, Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia.
Papillomavirus Res. 2018 Jun;5:6-20. doi: 10.1016/j.pvr.2017.10.001. Epub 2017 Oct 19.
Currently available vaccines prevent HPV infection and development of HPV-associated malignancies, but do not cure existing HPV infections and dysplastic lesions. Persistence of infection(s) in immunocompetent patients may reflect induction of local immunosuppressive mechanisms by HPV, providing a target for therapeutic intervention. We have proposed that a mouse, expressing HPV16 E7 oncoprotein under a Keratin 14 promoter (K14E7 mice), and which develops epithelial hyperplasia, may assist with understanding local immune suppression mechanisms that support persistence of HPV oncogene-induced epithelial hyperplasia. K14E7 skin grafts recruit immune cells from immunocompetent hosts, but consistently fail to be rejected. Here, we review the literature on HPV-associated local immunoregulation, and compare the findings with published observations on the K14E7 transgenic murine model, including comparison of the transcriptome of human HPV-infected pre-malignancies with that of murine K14E7 transgenic skin. We argue from the similarity of i) the literature findings and ii) the transcriptome profiles that murine K14E7 transgenic skin recapitulates the cellular and secreted protein profiles of high-grade HPV-associated lesions in human subjects. We propose that the K14E7 mouse may be an appropriate model to further study the immunoregulatory effects of HPV E7 expression, and can facilitate development and testing of therapeutic vaccines.
目前可用的疫苗可预防HPV感染及HPV相关恶性肿瘤的发生，但无法治愈现有的HPV感染和发育异常病变。免疫功能正常的患者中感染持续存在，可能反映了HPV诱导的局部免疫抑制机制，这为治疗干预提供了靶点。我们提出，一种在角蛋白14启动子（K14E7小鼠）控制下表达HPV16 E7癌蛋白并发生上皮增生的小鼠，可能有助于理解支持HPV癌基因诱导的上皮增生持续存在的局部免疫抑制机制。K14E7皮肤移植可从免疫功能正常的宿主招募免疫细胞，但始终不会被排斥。在此，我们综述了关于HPV相关局部免疫调节的文献，并将这些发现与已发表的关于K14E7转基因小鼠模型的观察结果进行比较，包括比较人类HPV感染的癌前病变与小鼠K14E7转基因皮肤的转录组。基于以下两方面的相似性，我们认为：一是文献研究结果，二是转录组图谱，即小鼠K14E7转基因皮肤概括了人类受试者中高级别HPV相关病变的细胞和分泌蛋白图谱。我们提出，K14E7小鼠可能是进一步研究HPV E7表达的免疫调节作用的合适模型，并且能够促进治疗性疫苗的开发和测试。
