DNA Vaccine Encoding HPV16 Oncogenes E6 and E7 Induces Potent Cell-mediated and Humoral Immunity Which Protects in Tumor Challenge and Drives E7-expressing Skin Graft Rejection

Chandra, Janin; Dutton, Julie L.; Li, Bo; Woo, Wai-Ping; Xu, Yixin; Tolley, Lynn; Yong, Michelle C.R.; Wells, James W.; Leggatt, Graham R.; Finlayson, Neil; Frazer, Ian H.

doi:10.1097/cji.0000000000000156

Cited by 47 publications

(40 citation statements)

References 44 publications

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“…We reason that the K14E7 immunosuppressive environment alters the ability of APCs to react against the persistent E7 antigen. Consistent with this hypothesis, Langerhans cells from K14E7 skin expressed higher levels of immunosuppressive molecules such as IDO1, arginase 1 and IL-10, but paradoxically expressed lesser major histocompatibility complex II (MHCII) and PD-1 ligand 1 (PD-L1) [85] . Additionally, APCs displayed impaired antigen presenting capabilities [86] , [87] ; and although K14E7 skin displayed higher absolute numbers of DCs compared to wild-type controls, there was an increase in relative proportions of CD103+ and CD11b+ DCs but reduced Langerhans cells [87] .…”

Section: Resultsmentioning

confidence: 58%

“…To our knowledge, there have been two reports on the use of combination immunotherapy involving PD-L1 blockade with HPV16 therapeutic vaccination in mouse models, eliciting improved anti-tumour responses in both cases [85] , [119] . However, vaccine studies showing efficacy against the transplantable TC-1 tumour cell line expressing HPV16 E6 and E7, despite promising results in mouse studies, have failed to predict effective responses in human clinical trials [4] .…”

Section: Discussionmentioning

confidence: 99%

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Murine HPV16 E7-expressing transgenic skin effectively emulates the cellular and molecular features of human high-grade squamous intraepithelial lesions

Tuong

Noske

Kuo

et al. 2018

Papillomavirus Research

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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.

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Section: Resultsmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Murine HPV16 E7-expressing transgenic skin effectively emulates the cellular and molecular features of human high-grade squamous intraepithelial lesions

Tuong

Noske

Kuo

et al. 2018

Papillomavirus Research

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“…In vitro studies involving human cell lines expressing HPV16 E7 Ags have shown that blockade of PD-1/PD-L1 signaling significantly enhanced CTL responses [93] , [130] . Pre-clinical studies have also demonstrated that the combination of HPV16 E7 DNA-based therapeutic vaccines with co-blockade of PD-1/PD-L1 signaling in E6- and E7-expressing transplantable TC-1 tumor bearing mice can significantly enhance the tumor -specific CTL response and improve tumor regression [134] , [135] , [136] . Currently, there are several clinical trials targeting blockade of PD-1/PD-L1 in HNSCCs and nivolumab (anti-PD1 antibody) has been approved by the FDA for the treatment of recurrent or metastatic HNSCC patients [110] , [137] .…”

Section: Chronic Hpv Infection Immunoregulatory Cytokine Milieu Andmentioning

confidence: 99%

Modulation of antigen presenting cell functions during chronic HPV infection

Bashaw

Leggatt

Chandra

et al. 2017

Papillomavirus Research

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High-risk human papillomaviruses (HR-HPV) infect basal keratinocytes, where in some individuals they evade host immune responses and persist. Persistent HR-HPV infection of the cervix causes precancerous neoplasia that can eventuate in cervical cancer. Dendritic cells (DCs) are efficient in priming/cross-priming antigen-specific T cells and generating antiviral and antitumor cytotoxic CD8+ T cells. However, HR-HPV have adopted various immunosuppressive strategies, with modulation of DC function crucial to escape from the host adaptive immune response. HPV E6 and E7 oncoproteins alter recruitment and localization of epidermal DCs, while soluble regulatory factors derived from HPV-induced hyperplastic epithelium change DC development and influence initiation of specific cellular immune responses. This review focuses on current evidence for HR-HPV manipulation of antigen presentation in dendritic cells and escape from host immunity.

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“…The construct was combined with PDL1 (immune check point blockade) and it further enhanced antitumor immunity. 27 A new approach for DNA based vaccine suggests the vector that encodes for a TAA (tumor associated antigen) and T-cell costimulatory molecules which can be used for initial priming and the other is for booster effect. Such innovative approaches have been used in other cancers for ensuring a more viable immune response against the TAAs but not yet been used for cervical cancer vaccine.…”

Section: Dna Vaccine Encoding Hpv16 (E6 and E7)mentioning

confidence: 99%

A Step towards Resolving the Mystery of HPV Vaccination: Breakthrough of Cervical Cancer

Bharadwaj

Gautam

Singhal

et al. 2018

ACP

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Cervical cancer is the second most prevalent cancer in women worldwide, with about 500,000 cases and over 270,000 deaths estimated annually. The disease is caused due to the persistent infection of one or more type of high risk HPVs in which HPV-16/18 are the most common. In India, HPV-16 is the most prevalent type of High risk HPV associated with cervical cancer risk. In the year 2006-2007, two VLP based prophylactic HPV vaccines, Gardasil and Cervarix came into the market. Recently in 2014, a new nonavalent vaccine Gardasil9 has been licensed as the improvised form of tetravalent Gardasil by FDA. Though HPV vaccines prevent its spread and persistence but they are insufficient in reverting or eliminating the already established invasive cancers. Besides, these vaccines are also having certain limitations which includes require refrigeration, higher cost, limited serotype and efficacy is person dependent. To overcome the limitations of the available vaccines, the development of second generation vaccines e.g. capsomere based vaccines, plant based edible vaccines, recombinant live-vector vaccines, protein and peptide based vaccines, multi-epitopic based vaccines and DNA-based vaccines is under way. These vaccines will be heat stable, cost effective and may apply both in prevention and also in the treatment of cancers. It has been stated that cervical cancer is detected mainly in women older than 35 years suggesting HPV infection at a younger age and slow progression to cancer at an older age. It is really difficult to promote vaccination for younger girls in countries like India to prevent the onset of the disease because of the cultural and prestigious issues related to STDs. So there is an urging need in India for the development of therapeutic vaccine for the eradication of the devastating disease as well as to meet the global responsibility of achieving herd immunity.

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DNA Vaccine Encoding HPV16 Oncogenes E6 and E7 Induces Potent Cell-mediated and Humoral Immunity Which Protects in Tumor Challenge and Drives E7-expressing Skin Graft Rejection

Abstract: Supplemental Digital Content is available in the text.

Cited by 47 publications

References 44 publications

Murine HPV16 E7-expressing transgenic skin effectively emulates the cellular and molecular features of human high-grade squamous intraepithelial lesions

Murine HPV16 E7-expressing transgenic skin effectively emulates the cellular and molecular features of human high-grade squamous intraepithelial lesions

Modulation of antigen presenting cell functions during chronic HPV infection

A Step towards Resolving the Mystery of HPV Vaccination: Breakthrough of Cervical Cancer

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