Human papillomavirus type 16 (HPV16) is the etiologic factor for
cervical cancer and a subset of
oropharyngeal cancers. Although several prophylactic
HPV vaccines are available, no effective therapeutic strategies to control active HPV diseases exist.
Tumor implantation models are traditionally used to study HPV-associated buccal
tumors. However, they fail to address precancerous phases of
disease progression and display tumor microenvironments distinct from those observed in patients. Previously, K14-E6/E7 transgenic mouse models have been used to generate spontaneous
tumors. However, the rate of
tumor formation is inconsistent, and the host often develops immune tolerance to the viral
oncoproteins. We developed a preclinical, spontaneous, HPV16+ buccal
tumor model using submucosal injection of oncogenic plasmids expressing HPV16-E6/E7, NRas G12V ,
luciferase, and sleeping beauty (SB)
transposase, followed by electroporation in the buccal mucosa. We evaluated responses to immunization with a pNGVL4a-CRT/E7(detox) therapeutic HPV
DNA vaccine and
tumor cell migration to distant locations. Mice transfected with plasmids encoding HPV16-E6/E7, NRas G12V ,
luciferase, and SB
transposase developed
tumors within 3 weeks. We also found transient anti-CD3 administration is required to generate
tumors in immunocompetent mice. Bioluminescence signals from
luciferase correlated strongly with
tumor growth, and
tumors expressed HPV16-associated markers. We showed that pNGVL4a-CRT/E7(detox) administration resulted in antitumor immunity in
tumor-bearing mice. Lastly, we demonstrated that the generated
tumor could migrate to
tumor-draining lymph nodes. Our model provides an efficient method to induce spontaneous HPV+
tumor formation, which can be used to identify effective therapeutic interventions, analyze
tumor migration, and conduct
tumor biology research.
Cancer Immunol Res; 6(3); 305-19. ©2018 AACR.