An Immunocompetent Mouse Model of HPV16(+) Head and Neck Squamous Cell Carcinoma

SUMMARY

The incidence of human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is increasing and implicated in more than 60% of all oropharyngeal carcinomas (OPSCCs). Although whole-genome, transcriptome, and proteome analyses have identified altered signaling pathways in HPV-induced HNSCCs, additional tools are needed to investigate the unique pathobiology of OPSCC. Herein, bioinformatics analyses of human HPV(+) HNSCCs revealed that all tumors express full-length E6 and identified molecular subtypes based on relative E6 and E7 expression levels. To recapitulate the levels, stoichiometric ratios, and anatomic location of E6/E7 expression, we generated a genetically engineered mouse model whereby balanced expression of E6/E7 is directed to the oropharyngeal epithelium. The addition of a mutant PIK3CA ^E545K allele leads to the rapid development of pre-malignant lesions marked by immune cell accumulation, and a subset of these lesions progress to OPSCC. This mouse provides a faithful immunocompetent model for testing treatments and investigating mechanisms of immuno- suppression.

Graphical Abstract

In Brief

Carper et al. present the ‘‘iKHP’’ mouse, in which HPV16 oncogenes are inducibly activated in vivo in a tissue-specific and temporal manner. Oropharyngeal- specific expression of E6/E7 with PIK3CA ^E545K in these mice promotes the development of premalignant lesions marked by immune cell infiltration, but only a subset spontaneously convert to OPSCC.