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* Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA 92647;
Department of Neurology, Institute for Brain Aging and Dementia, University of California, Irvine, CA 92697;
Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; and
OncoMune Inc., Miami, FL 33122
Brother of the regulator of imprinted sites (BORIS) was previously described as a transcription factor for epigenetic reprogramming the expression of which is strictly confined to germ cells of adult testes but is aberrantly activated in the vast majority of neoplastic cells. Considering the critical role of BORIS in cancerogenesis and the fact that its expression pattern may preclude thymic tolerance, we generated DNA- and protein-based mouse BORIS antitumor vaccines using a non-DNA-binding version of the BORIS molecule. Clinical use of BORIS as a vaccine Ag would require that certain safety concerns be met. Specifically, administration of the functional BORIS protein would hypothetically pose a risk of BORIS accelerating the progression of cancer. To alleviate such safety concerns, we have developed vaccines based on the BORIS molecule lacking the DNA-binding zinc fingers domain. To enhance anti-BORIS cellular immune responses, we used a standard molecular adjuvant approach. It consisted of plasmids encoding murine IL-12 and IL-18 for a DNA-based vaccine and conventional Th1 type adjuvant, Quil A, for a protein-based vaccine. Both DNA- and protein-based vaccines induced Ag-specific CD4+ T cell proliferation with Th1 and Th2 cytokine profiles, respectively. Protein-based, but not DNA-based, BORIS vaccine induced a significant level of Ab production in immunized animals. Importantly, potent anticancer CD8+-cytotoxic lymphocytes were generated after immunization with the DNA-based, but not protein-based, BORIS vaccine. These cytolytic responses were observed across a wide range of different mouse cancers including mammary adenocarcinoma, glioma, leukemia, and mastocytoma.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants RO1 AI-44809, RO1 AG-20241, and RO1 NS-050895.
2 A.G., M.M., and D.L. contributed equally to this paper.
3 Address correspondence and reprint requests to Dr. Michael G. Agadjanyan, Institute for Molecular Medicine, 16371 Gothard Street, H, Huntington Beach, CA 92647-3652. E-mail address: magadjanyan{at}immed.org
4 Abbreviations used in this paper: TAA, tumor-associated Ag; BORIS, brother of the regulator of imprinted sites; CTCF, CCCTC-binding factor; pmBORIS, plasmid encoding the truncated mouse BORIS molecule; mBORIS, mouse mutated BORIS; CT, cancer-testis; DC, dendritic cell; PTD, protein transduction domain.
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  S. Renaud, E. M. Pugacheva, M. D. Delgado, R. Braunschweig, Z. Abdullaev, D. Loukinov, J. Benhattar, and V. Lobanenkov Expression of the CTCF-paralogous cancer-testis gene, brother of the regulator of imprinted sites (BORIS), is regulated by three alternative promoters modulated by CpG methylation and by CTCF and p53 transcription factors Nucleic Acids Res., December 18, 2007; 35(21): 7372 - 7388. [Abstract] [Full Text] [PDF]
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