A therapeutic vaccine targeting HPV E6/E7 with intrinsic Toll-like receptor 2 agonist activity induces antitumor immunity.

The E6 and E7 oncoproteins of human papillomavirus (HPV) are ideal targets for developing immunotherapeutic approaches to treat HPV-associated tumors. Our previous studies showed that a recombinant lipidated HPV16 E7 mutant (rlipo-E7m) with inactivation of the E7 oncogenic functions can activate antigen presenting cells through Toll-like receptor 2 (TLR2) and induce antitumor immunity. Given that some HPV-associated tumors overexpress E6 but not E7, it is necessary to include therapeutic agents containing HPV E6 in therapeutic vaccine development to broaden the utility of the vaccine. In this study, we further incorporated a mutant HPV16 E6 (E6m) into rlipo-E7m to generate rlipo-E6mE7m, which could elicit both E6- and E7-specific immune responses after immunization. The rlipo-E6mE7m immunization induced higher levels of T cell proliferation and cytotoxic T lymphocyte response than the nonlipidated recombinant E6mE7m (rE6mE7m) immunization. Accordingly, a single-dose administration of rlipo-E6mE7m at day 7 after tumor inoculation in mice showed complete inhibition of tumor growth, whereas administration of rE6mE7m did not. These results demonstrated that rlipo-E6mE7m could be used in tumors with E6 and/or E7 expression via the induction of E6- and E7-specific immunity.