Abstract 3999: Altering the balance between immune activation versus regulation in the skin to promote CD8 T-cell activity within epithelial cancers

Abstract

Abstract The Human Papilloma Virus (HPV) 16 is a high-risk HPV known to be a causative agent in numerous cancers including cervical cancer. While prophylactic vaccines exist to combat the spread of HPV16, successful therapeutic vaccines to combat established HPV16-associcated disease remain elusive. The expression, in a mouse model (“E7”), of the HPV16 E7 gene in keratinocytes under the control of the K14 promoter, leads to a local immune suppressive environment, as evidenced by the lack of graft rejection when E7 skin grafts are placed on WT recipient mice. Furthermore, well healed (>30 days) E7 skin grafts are not rejected when mice are immunised with E7 peptide in combination with Quil A- or CASAC-based adjuvants. This is despite a substantial increase in E7 peptide/H-2Db pentamer staining in the blood, and marked killing of E7-peptide expressing TC-1 cells when injected i.v., confirming that CD8 T-cells respond to vaccination and differentiate into CTL capable of killing E7-expressing target cells. We hypothesised that the removal of regulatory T-cells (T-reg) might lead to E7 graft rejection in immunised mice. The co-administration of an anti-CD4-depeting antibody at the time of immunisation led to rejection of ∼50% of grafts. To confirm a role for T-reg, E7-grafted T-reg-deficient Rag1-/- mice received purified donor CD8 T-cells from E7-vaccinated WT mice. FACS staining of Rag1-/- lymph nodes 30 days post CD8+ T-cell transfer confirmed the absence of classical CD4+FoxP3+ Treg, however the E7 grafts did not reject. As in the WT mice however, rejection could be induced through the co-administration of an anti-CD4 antibody. The data suggest that the removal of a CD4+, non T-reg cell, leads to CD8+ T-cell activity in the skin as evidenced by E7 skin graft destruction. Citation Format: Jennifer A. Bridge, Nana H. Overgaard, Raymond J. Steptoe, Ian H. Frazer, James W. Wells. Altering the balance between immune activation versus regulation in the skin to promote CD8 T-cell activity within epithelial cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3999.