Studies of therapeutic vaccination and immune evasion by human papillomavirus oncoproteins

Recent trials of prophylactic vaccination for cervical cancer have been very promising but these vaccines do not protect women already infected with high-risk human papillomavirus (HPV) types. Immunotherapy targeting high-risk HPV lesions have the potential to benefit the estimated 5 million women already infected who will succumb to the disease over the next 20 years even as prophylactic vaccines are implemented. Salmonella delivery of antigens via type III secretion and a recombinant attenuated form of vesicular stomatitis virus (VSV), a single-stranded RNA virus, have been developed as vectors for experimental therapeutic vaccines. Furthermore, any immunotherapy strategy must contend with potential viral strategies that have evolved to evade host immune responses. To study this, we examined the role of HPV 16 E5 in the downregulation of MHC class I surface expression.; Oral vaccination with attenuated strains of Salmonella secreting HPV 16 E7 as a chimera with a bacterial effector protein generated modest antitumor responses in a mouse model of cervical cancer. However, we did not detect HPV 16 E7-specific T cells. We then turned to VSV to express HPV 16 E7 as an antigen for therapeutic vaccination. By 14 days post-therapeutic vaccination with VSV expressing HPV 16 E7, average tumor volumes were 6-fold less in the HPV 16 E7 treatment group compared to mice that received the empty vector VSV. Use of gene deficient mice showed that the antitumor effect is CD8 T cell dependent. HPV 16 E7 specific T cells with cytotoxic activity were detected by various immune assays. Attempts to combine Salmonella and VSV in a heterologous prime and boost strategy did not show any improvement over the single dose VSV vaccination.; We demonstrated downregulation of surface MHC class I molecules in clonal TC-1 tumor cell lines, a mouse model for cervical cancer, by expressing a codon-optimized HPV 16 E5. Pooled SiHa cells, a HPV 16 human cervical cancer line, also downregulated surface MHC class I with overexpression of HPV 16 E5. However, use of TC-1 cells with and without HPV 16 E5 as targets in cytotoxic T cell assays did not demonstrate a significant difference.; Our results demonstrated anti-tumor responses to VSV HPV 16 E7 in a mouse model for cervical cancer. These results suggest that recombinant VSV-based vaccination should be further explored as a therapeutic strategy for cervical cancer.