Inducing Immunity Where It Matters: Orthotopic HPV Tumor Models and Therapeutic Vaccinations

Abstract

Anogenital and oropharyngeal cancers caused by human papillomavirus (HPV) infections account for 4.5% of all cancer cases worldwide. So far, only the initial infection with selected high-risk types can be prevented by prophylactic vaccination. Already existing persistent HPV infections, however, can currently only be treated by surgical removal of resulting lesions. Therapeutic HPV vaccination, promoting cell-based anti-HPV immunity, would be ideal to eliminate and protect against HPV-induced lesions and tumors. A multitude of vaccination approaches has been tested to date, many of which led to high amounts of HPV-specific T cells in vivo. However, growing evidence suggests that not the induction of systemic but of local immunity is paramount for tackling mucosal infections and tumors. Therefore, recent therapeutic vaccination studies have focused on how to induce tissue-resident T cells in the anogenital and oropharyngeal mucosa. These approaches include direct mucosal vaccinations and influencing the migration of systemic T cells toward the mucosa. The efficacy of these new vaccination approaches is best tested in vivo by utilizing orthotopic tumor models, i.e. HPV-positive tumors being located in the animal's mucosa. In line with this, we here review existing HPV tumor models and describe two novel tumorigenic cell lines for the MHC-humanized mouse model A2.DR1. These were used for the establishment of an HPV16 E6/E7-positive vaginal tumor model, suitable for testing therapeutic vaccines containing HLA-A2-restricted HPV16-derived epitopes. The newly developed MHC-humanized orthotopic HPV16-positive tumor model is likely to improve the translatability of in vivo findings to the clinical setting.

Effects of hypoxia on antigen presentation and T cell-based immune recognition of HPV16-transformed cells

“…Additionally, they are most commonly studied in a subcutaneous setting, which does not resemble the mucosal environment. Only a few recent studies use tumor models in an orthotopic setting (47). Finally, and most importantly, murine cells do not present clinically relevant HLA-restricted epitopes, preventing direct examination of relevant peptides.…”

Murine Models of Chronic Viral Infections and Associated Cancers

“…Other completely MHC-humanized mice were obtained more recently to study the HLA-restricted peptide recognition without interference of epitope presentation in the context of mouse MHC molecules [ 68 ]. In the humanized A2.DR1 model, the HLA molecules most common in Caucasians (HLA-A*0201: the epitope-binding domains α1 and α2 of HLA-A*0201 with the α3 domain of H-2D b , covalently bound with human β2m (HDD)) and HLA-DR1 are expressed, while all murine MHC genes are not as a result of a knockout.…”

“…In the humanized A2.DR1 model, the HLA molecules most common in Caucasians (HLA-A*0201: the epitope-binding domains α1 and α2 of HLA-A*0201 with the α3 domain of H-2D b , covalently bound with human β2m (HDD)) and HLA-DR1 are expressed, while all murine MHC genes are not as a result of a knockout. The model was used to test vaccines against HPV 16; HPV infection was modeled by grafting syngenic cell lines expressing the E6 and E7 proteins [ 68 ]. For example, a transgenic cell line oncogenic for HLA-A*0201 mice was obtained by transfecting heart and lung fibroblasts from HLA-A*0201-transgenic mice with the H-Ras V12 oncogene and the Е6 and Е7 genes of HPV 16.…”

A model for long-term infection of bovine papillomavirus type 1 in Saccharomyces cerevisiae

“…Considering that the preventive vaccines are unable to wipe out the existing HPV viruses in already infected people, scientists have been focusing on Acta virologica 65: 2021 doi: 10.4149/av_2021_204 3 developing the therapeutic HPV vaccines that have reached the clinical trial phase in cervical cancers and diseases. Many therapeutic HPV vaccines tested in clinical trials show the potential use of the vaccines as safe and effective pharmacological tools (Zhang et al, 2020;Zottnick et al, 2020). Development of the potential therapeutic vaccines for HPV infection is a very exciting area of HPV research.…”