DNA vaccines encoding altered peptide ligands for SSX2 enhance epitope-specific CD8+ T-cell immune responses.
Plasmid DNA serves as a simple and easily modifiable form of antigen delivery for vaccines. The USDA approval of DNA vaccines for several non-human diseases underscores the potential of this type of antigen delivery method as a cost-effective approach for the treatment or prevention of human diseases, including cancer. However, while DNA vaccines have demonstrated safety and immunological effect in early phase clinical trials, they have not consistently elicited robust anti-tumor responses. Hence many recent efforts have sought to increase the immunological efficacy of DNA vaccines, and we have specifically evaluated several target antigens encoded by DNA vaccine as treatments for human prostate cancer. In particular, we have focused on SSX2 as one potential target antigen, given its frequent expression in metastatic prostate cancer. We have previously identified two peptides, p41-49 and p103-111, as HLA-A2-restricted SSX2-specific epitopes. In the present study we sought to determine whether the efficacy of a DNA vaccine could be enhanced by an altered peptide ligand (APL) strategy wherein modifications were made to anchor residues of these epitopes to enhance or ablate their binding to HLA-A2. A DNA vaccine encoding APL modified to increase epitope binding elicited robust peptide-specific CD8+ T cells producing Th1 cytokines specific for each epitope. Ablation of one epitope in a DNA vaccine did not enhance immune responses to the other epitope. These results demonstrate that APL encoded by a DNA vaccine can be used to elicit increased numbers of antigen-specific T cells specific for multiple epitopes simultaneously, and suggest this could be a general approach to improve the immunogenicity of DNA vaccines encoding tumor antigens.
Department of Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA.
Heath A
HA
Smith
Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Brian T
BT
Rekoske
Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA. Electronic address: dm3@medicine.wisc.edu.
Douglas G
DG
McNeel
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D011471:Prostatic Neoplasms / Q000628:therapy; D012097:Repressor Proteins / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology*
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D008024:Ligands; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D012097:Repressor Proteins; D019444:Vaccines, DNA; C093962:synovial sarcoma X breakpoint proteins
APL; CTA; DNA vaccine; Prostate cancer; SSX