Abstract
BACKGROUND: High-risk human papillomavirus (HPV), especially HPV16, is closely correlated with certain cancers. E6 and E7 proteins of HPV16 play critical roles in oncogenesis, making them optimal targets for treating HPV-associated cancers. Here, we engineered an innovative vaccine, Ad-E6/7-HR, designed to evoke immune responses through the incorporation of self-assembling heptad-repeat 1 (HR1) and HR2 originated from Severe acute respiratory syndrome coronavirus 2. METHODS: Ad-E6/7-HR was constructed utilising a replication-defective human adenovirus serotype 5 vector and evaluated its immunogenicity and therapeutic efficacy in murine models. We verified the antitumour efficacy of the vaccine in TC-1 subcutaneous and pulmonary models. Flow cytometry, enzyme-linked immunospot assay, and immunofluorescence staining were used to assess the cellular immunogenicity of Ad-E6/7-HR. RESULTS: Ad-E6/7-HR induced robust immune responses, significantly increasing antigen-specific CD8(+) T cells. The vaccine also enhanced memory T-cell generation and induced potent cytokine secretion, as exemplified by interferon-γ and tumour necrosis factor-α. Ad-E6/7-HR conferred complete protection against tumour growth in the prophylactic model. In therapeutic settings, Ad-E6/7-HR significantly reduced tumour size and improved survival. Furthermore, Ad-E6/7-HR reshaped the tumour microenvironment by increased CD8(+) T-cell recruitment and reduced immunosuppressive cells, like myeloid-derived suppressor cells and M2 macrophages, thereby enhancing antitumour immunity. CONCLUSIONS: By targeting HPV16 E6 and E7 proteins and leveraging the self-assembling HR1 and HR2 sequences to enhance immune responses, Ad-E6/7-HR represented a promising candidate for preventing and treating HPV-associated cancers. Further clinical investigation is warranted to evaluate its potential in human trials.