Antitumor efficacy of DNA vaccination to the epigenetically acting tumor promoting transcription factor BORIS and CD80 molecular adjuvant.
Cancer testis (CT) antigens are promising candidates for tumor vaccines due to their immunogenicity and tissue-restricted expression. Recently, we identified a novel cancer testis gene, BORIS, whose expression is restricted to male testis after puberty and is strictly absent in non-malignant female tissue. BORIS encodes a DNA-binding protein that shares 11 zing finger (ZF) with transcription factor CTCF and differs at the N- and C-termini. CTCF has been implicated in epigenetic regulation of imprinting, X chromosome inactivation, repression, and activation of cancer testis antigens. BORIS expression has been documented in cancers of diverse histological origin, including, but not limited to breast, prostate, ovary, gastric, liver, endometrial, glia, colon, and esophagus. Interestingly, BORIS induces demethylation and subsequent expression of many cancer-testis genes, including MAGE-A1 and NY-ESO-1, indicating that it is expressed very early in malignancy and might be an attractive candidate for immunotherapy. In this study we tested BORIS as a vaccine in a very aggressive, highly metastatic, and poorly immunogenic murine model of mammary carcinoma. Immunizations with a DNA encoding the mutant form of murine BORIS antigen (pmBORIS lacking DNA-binding function) significantly prolonged survival, and inhibited tumor growth in BALB/c mice inoculated with 4T1 cells. Priming with pmBORIS mixed with molecular adjuvant and boosting with adenoviral vector expressing mBORIS was generally more effective, suggesting that the vaccination protocol could be further optimized. This is the first report demonstrating the feasibility of vaccination with a cancer associated epigenetic regulator for the induction of tumor inhibition.
Loukinov
Dmitri
D
National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
Ghochikyan
Anahit
A
Mkrtichyan
Mikayel
M
Ichim
Thomas E
TE
Lobanenkov
Victor V
VV
Cribbs
David H
DH
Agadjanyan
Michael G
MG
D000276:Adjuvants, Immunologic; D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology*; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D006224:Cricetinae; D004247:DNA / Q000235:genetics* / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D014611:Vaccination
D000276:Adjuvants, Immunologic; D018122:B7-1 Antigen; D019496:Cancer Vaccines; C499208:Ctcfl protein, mouse; D004268:DNA-Binding Proteins; D004247:DNA