A novel dendritic cell targeting HPV16 E7 synthetic vaccine in combination with PD-L1 blockade elicits therapeutic antitumor immunity in mice

Abstract

Human papilliomavirus (HPV) oncogene E7, essential for the transformation and maintenance of the malignancy of cervical cancer cells, represents an ideal tumor-specific antigen for vaccine development. However, due to the poor immunogenicity of E7 protein, an effective therapeutic E7 vaccine is still lacking. Dendritic cells (DCs) are probably the most potent antigen presenting cells for the induction of cytotoxic T lymphocyte (CTL) response, which is crucial for tumor control. In this study, we tested whether targeting the E7 antigen to DCs in vivo would elicit therapeutic antitumor CTL response. We generated the DEC205-specific single-chain variable fragment (scFv) and E7 long peptide fusion protein [scFv(DEC205)-E7] based on the novel method of protein assembly we recently developed. This fusion protein vaccine demonstrated highly efficient DC-targeting in vivo and elicited much stronger protective CTL response than non-DC-targeting control vaccine in naive mice. Furthermore, the scFv(DEC205)-E7 vaccine showed significant therapeutic antitumor response in TC-1 tumor bearing mice. Importantly, PD-L1 blockade further improved the therapeutic effect of the scFv(DEC205)-E7 vaccine. Thus, the current study suggests an efficient strategy for cervical cancer immunotherapy by combining the DC(DEC205)-targeting E7 vaccine and PD-L1 blockade.

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

“…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] .…”

Recent advances in preclinical model systems for papillomaviruses

“…In particular, mouse cell lines that express various HPV viral oncogenes have been used to examine improved antigen presentation strategies (Cheng, Hung et al, 2003), define the role of CD8 T-cells in tumor control (Hung, Cheng et al, 2003; Beyranvand, van der Sluis et al, 2016), assess check-point inhibitors that alleviate T-cell exhaustion (Liu, Zhou et al, 2016; Mkrtichyan, Chong et al, 2013) and improve vaccine efficacy (Song, Yang et al, 2014; Peng, Qiu et al, 2016; Soong, Song et al, 2014). …”

A STING-activating nanovaccine for cancer immunotherapy

“…4e). Finally, we employed human papilloma virus (HPV) E6/7 TC-1 tumors 28,29 . Using an E7-derived peptide E7 43-62 , 50% of mice are tumor free 60 days after treatment with E7 43-62 -PC7A NP (Fig.…”