title: A DNA vaccine encoding a single-chain trimer of HLA-A2 linked to human mesothelin peptide generates anti-tumor effects against human mesothelin-expressing tumors.
abstract: Mesothelin is highly expressed in a majority of ovarian cancer cells and is expressed at low levels in normal cells. Therefore, mesothelin represents a potential target antigen for ovarian cancer vaccine development. DNA vaccines employing single-chain trimers (SCT) have been shown to bypass antigen processing and presentation and result in significant enhancement of DNA vaccine potency. In the current study, we created a DNA vaccine employing an SCT targeting human mesothelin and characterized the ensuing antigen-specific CD8+ T cell-mediated immune responses and anti-tumor effects against human mesothelin-expressing tumors in HLA-A2 transgenic mice. Our results showed that vaccination with DNA employing an SCT of HLA-A2 linked to human mesothelin epitope aa540-549 (pcDNA3-Hmeso540-beta2m-A2) generated strong human mesothelin peptide (aa540-549)-specific CD8+ T cell immune responses in HLA-A2 transgenic mice. Vaccination with pcDNA3-Hmeso540-beta2m-A2 prevented the growth of HLA-A2 positive human mesothelin-expressing tumor cell lines in HLA-A2 transgenic mice in contrast to vaccination with DNA encoding SCT linked to OVA CTL epitope. Thus, the employment of SCT of HLA-A2 linked to the human mesothelin epitope aa540-549 represents a potential opportunity for the clinical translation of DNA vaccines against human mesothelin-expressing tumors, particularly ovarian cancer cells.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA. chung2@jhmi.edu
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.forename: Roanne
authors.initials: R
authors.lastname: Calizo
authors.forename: Ya-Chea
authors.initials: YC
authors.lastname: Tsai
authors.forename: Liangmei
authors.initials: L
authors.lastname: He
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte; D005260:Female; D058851:GPI-Linked Proteins; D015789:HLA-A2 Antigen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D000090204:Mesothelin; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms / Q000276:immunology / Q000517:prevention & control*; D010455:Peptides / Q000737:chemistry; D014611:Vaccination; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D058851:GPI-Linked Proteins; D015789:HLA-A2 Antigen; D008562:Membrane Glycoproteins; C000715528:Msln protein, mouse; D010455:Peptides; D019444:Vaccines, DNA; D000090204:Mesothelin