This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sewell, D. A. Articles by Paterson, Y. Search for Related Content PubMed PubMed Citation Articles by Sewell, D. A. Articles by Paterson, Y.

Recombinant Listeria Vaccines Containing PEST Sequences Are Potent Immune Adjuvants for the Tumor-Associated Antigen Human Papillomavirus-16 E7

¹ Department of Microbiology and the University of Pennsylvania Cancer Center, and ² Department of Otorhinolaryngology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Previous work in our laboratory has established that the fusion of tumor-associated antigens to a truncated form of the Listeria monocytogenes virulence factor listeriolysin O (LLO) enhances the immunogenicity and antitumor efficacy of the tumor antigen when delivered by Listeria or by vaccinia. LLO contains a PEST sequence at the NH₂ terminus. These sequences, which are found in eukaryotic proteins with a short cellular half-life, target proteins for degradation in the ubiquitin-proteosome pathway. To investigate whether the enhanced immunogenicity conferred by LLO is due to the PEST sequence, we constructed new Listeria recombinants that expressed the HPV-16 E7 antigen fused to LLO, which either contained or had been deleted of this sequence. We then compared the antitumor efficacy of this set of vectors and found that Listeria expressing the fusion protein LLO-E7 or PEST-E7 were effective at regressing established macroscopic HPV-16 immortalized tumors in syngeneic mice. In contrast, Listeria recombinants expressing E7 alone or E7 fused to LLO from which the PEST sequence had been genetically removed could only slow tumor growth. Because CD8⁺ T cell epitopes are generated in the ubiquitin-proteosome pathway, we also investigated the ability of the vaccines to induce E7-specific CD8⁺ T cells in the spleen and to generate E7-specific tumor-infiltrating lymphocytes. A strong correlation was observed between CD8⁺ T-cell induction and tumor homing and the antitumor efficacy of the Listeria-E7 vaccines. These findings suggest a strategy for the augmentation of tumor antigen-based immunotherapeutic strategies that may be broadly applicable.

This article has been cited by other articles:

				P. C. Maciag, M. M. Seavey, Z.-K. Pan, S. Ferrone, and Y. Paterson Cancer Immunotherapy Targeting the High Molecular Weight Melanoma-Associated Antigen Protein Results in a Broad Antitumor Response and Reduction of Pericytes in the Tumor Vasculature Cancer Res., October 1, 2008; 68(19): 8066 - 8075. [Abstract] [Full Text] [PDF]

				B. Huang, J. Zhao, S. Shen, H. Li, K.-L. He, G.-X. Shen, L. Mayer, J. Unkeless, D. Li, Y. Yuan, et al. Listeria monocytogenes Promotes Tumor Growth via Tumor Cell Toll-Like Receptor 2 Signaling Cancer Res., May 1, 2007; 67(9): 4346 - 4352. [Abstract] [Full Text] [PDF]

				R. Singh and Y. Paterson Vaccination Strategy Determines the Emergence and Dominance of CD8+ T-Cell Epitopes in a FVB/N Rat HER-2/neu Mouse Model of Breast Cancer. Cancer Res., August 1, 2006; 66(15): 7748 - 7757. [Abstract] [Full Text] [PDF]

				K. B. Gendron, A. Rodriguez, and D. A. Sewell Vaccination with human papillomavirus type 16 e7 Peptide with CpG oligonucleotides for prevention of tumor growth in mice. Arch Otolaryngol Head Neck Surg, March 1, 2006; 132(3): 327 - 332. [Abstract] [Full Text] [PDF]

				R. Singh, M. E. Dominiecki, E. M. Jaffee, and Y. Paterson Fusion to Listeriolysin O and Delivery by Listeria monocytogenes Enhances the Immunogenicity of HER-2/neu and Reveals Subdominant Epitopes in the FVB/N Mouse J. Immunol., September 15, 2005; 175(6): 3663 - 3673. [Abstract] [Full Text] [PDF]