Reversal of Human Papillomavirus-Mediated Suppression of Langerhans Cells Function with the TLR3 Agonist Poly-ICR (53.7)

Abstract The human papillomavirus (HPV) family of viruses establishes persistent infections because it has evolved mechanisms that allow it to evade the human immune system. We have identified HPV-mediated suppression of antigen presentation by Langerhans cells (LC) as a key mechanism through which HPV evades immune surveillance. PolyICR is a stable TLR3 agonist that is a broad inducer of innate immunity and is being developed as a vaccine adjuvant and antitumor agent. An important feature of PolyICR is its ability to functionally activate dendritic cells to induce antigen-specific T cells. In this study, we determined whether PolyICR can overcome HPV-induced immune suppression by functionally activating human LC in the presence of HPV16 and inducing HPV16-specific T cells. PolyICR was able to activate LC that had been pre-exposed to HPV16 VLP such that expression of MHC and costimulatory molecules were highly upregulated and LC secreted high amounts of Th1 and inflammatory cytokines and chemokines. Upregulation of CCR7 resulted in a significant increase in migration capacity. LC incubated with HPV16 VLP and treated with PolyICR induced an HPV16-specific CD8+ T cell response detected by interferon gamma Elispot that was absent when LC were exposed to VLP alone. These data suggest that the TLR3 agonist PolyICR is a promising therapeutic molecule that can overcome HPV-induced immune suppression of LC and result in an LC capable of stimulating an anti-HPV T-cell mediated immune response.