Control of Spontaneous HPV16 E6/E7 Expressing Oral Cancer in HLA-A2 (AAD) Transgenic Mice with Therapeutic HPV DNA Vaccine.

Abstract

BACKGROUND:

Human Papillomavirus type 16 (HPV16) has been associated with a subset of head and neck cancers. Two HPV encoded oncogenic proteins, E6 and E7, are important for the malignant progression of HPV-associated cancers. A spontaneous HPV16 E6/E7-expressing oral tumor model in human HLA-A2 (AAD) transgenic mice will be important for the development of therapeutic HPV vaccines for the control of HPV-associated head and neck cancers.

METHODS:

In the current studies, we characterized the HLA-A2 restricted HPV16 E7-specific CD8 + T cell mediated immune responses in the HLA-A2 (AAD) transgenic mice using a therapeutic naked DNA vaccine encoding calreticulin (CRT) linked to a mutated E7(N53S). We also employed oncogenic DNA plasmids that encoded HPV16E6/E7/Luc, NRasG12V, and sleeping beauty transposase for the transfection into the submucosal of oral cavity of the transgenic mice with electroporation to create a spontaneous oral tumor. Furthermore, we characterized the therapeutic antitumor effects of CRT/E7(N53S) DNA vaccine using the spontaneous HPV16 E6/E7-expressing oral tumor model in HLA-A2 (AAD) transgenic mice.

RESULTS:

We found that CRT/E7(N53S) DNA vaccine primarily generated human HPV16 E7 peptide (aa11-20) specific CD8 + T cells, as compared to the wild-type CRT/E7 vaccine, which primarily generated murine H-2Db restricted E7 peptide (aa49-57) specific CD8 + T cell responses. We also observed transfection of the oncogenic DNA plasmids with electroporation generated spontaneous oral tumor in all of the injected mice. Additionally, treatment with CRT/E7(N53S) DNA vaccine intramuscularly followed by electroporation resulted in significant antitumor effects against the spontaneous HPV16 E6/E7-expressing oral tumors in HLA-A2 (AAD) transgenic mice.

CONCLUSIONS:

Taken together, the data indicated that the combination of HPV16 E6/E7-expressing DNA, NRasG12V DNA and DNA encoding sleeping beauty transposase is able to generate spontaneous oral tumor in HLA-A2 (AAD) transgenic mice, which can be successfully controlled by treatment with CRT/E7(N53S) DNA vaccine. The translational potential of our studies are discussed.

• Authors: Ssu-Hsueh Tseng, Li Liu, Shiwen Peng, Jinhwi Kim, Louise Ferrall, Chien-Fu Hung, T -C Wu
• Journal: Journal of biomedical science (J Biomed Sci) Vol. 28 Issue 1 Pg. 63 (Sep 13 2021) ISSN: 1423-0127 [Electronic] England
• PMID: 34517865 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• E6 protein, Human papillomavirus type 16
• HLA-A2 Antigen
• Oncogene Proteins, Viral
• Papillomavirus Vaccines
• Repressor Proteins

Topics

• Animals
• HLA-A2 Antigen (genetics)
• Mice
• Mice, Transgenic
• Mouth Neoplasms (genetics, prevention & control)
• Oncogene Proteins, Viral (metabolism)
• Papillomavirus Infections (prevention & control)
• Papillomavirus Vaccines (therapeutic use)
• Repressor Proteins (metabolism)