Introduction

For development of effective cancer vaccines, tumor antigens need to be identified that are either tumor-specific or selectively overexpressed in tumors. The cyclin-dependent kinase inhibitor p16^INK4a may be an almost ideal target structure, because it is strongly overexpressed in human papillomavirus (HPV)-induced cancers, but is barely detectable in normal tissue. Moreover, p16^INK4a is not only expressed in HPV dependent tumors, but also in a large fraction of non-HPV-related tumor entities such as colorectal cancer and small cell lung cancer, marking p16^INK4a as a broad tumor antigen.

Methods

In order to develop a p16^INK4a-based vaccine, two different mouse models were used: 1) C57Bl/6 mice were vaccinated with murine p16^INK4a-derived peptides to evaluate the induction of humoral and cellular immune responses and 2) FoxP3-DTR mice were immunized with p16^INK4a-derived peptides after depletion of Tregs and challenged with HPV-induced, p16^INK4a-expressing TC-1 cells to analyze the anti-tumor effect.

Results

Antibodies as well as CD4⁺ and CD8⁺ T cell responses were induced by immunization of C57Bl/6 mice with p16^INK4a-derived peptides showing that there is no or no complete tolerance against the murine self-antigen p16^INK4a. A more vigorous CD8⁺ T cell response against p16^INK4a was obtained in Treg-depleted FoxP3-DTR mice resulting in partial rejection of TC-1 tumors.

Conclusions

These data demonstrate for the first time that a p16^INK4a-positive tumor can be eradicated by p16^INK4a vaccination, provided that the immune response is of sufficient strength.

The generation of effective anti-tumor responses against p16^INK4a could lead to a new therapeutic approach for HPV-induced cancers as well as for tumors overexpressing p16^INK4a independent of an HPV infection.