Immunity from NK Cell Subsets Is Important for Vaccine-Mediated Protection in HPV+ Cancers

High-risk human papillomaviruses (HPVs) are associated with genital and oral cancers, and the incidence of HPV+ head and neck squamous cell cancers is fast increasing in the USA and worldwide. Survival rates for patients with locally advanced disease are poor after standard-of-care chemoradiation treatment. Identifying the antitumor host immune mediators important for treatment response and designing strategies to promote them are essential. We reported earlier that in a syngeneic immunocompetent preclinical HPV tumor mouse model, intranasal immunization with an HPV peptide therapeutic vaccine containing the combination of aGalCer and CpG-ODN adjuvants (TVAC) promoted clearance of HPV vaginal tumors via induction of a strong cytotoxic T cell response. However, TVAC was insufficient in the clearance of HPV oral tumors. To overcome this deficiency, we tested substituting aGalCer with a clinically relevant adjuvant QS21 (TVQC) and observed sustained, complete regression of over 70% of oral and 80% of vaginal HPV tumors. The TVQC-mediated protection in the oral tumor model correlated with not only strong total and HPV-antigen-specific CD8 T cells, but also natural killer dendritic cells (NKDCs), a novel subset of NK cells expressing the DC marker CD11c. Notably, we observed induction of significantly higher overall innate NK effector responses by TVQC relative to TVAC. Furthermore, in mice treated with TVQC, the frequencies of total and functional CD11c+ NK cell populations were significantly higher than the CD11c- subset, highlighting the importance of the contributions of NKDCs to the vaccine response. These results emphasize the importance of NK-mediated innate immune effector responses in total antitumor immunity to treat HPV+ cancers.