Elicitation of T cell responses to histologically unrelated tumors by immunization with the novel cancer-testis antigen, brother of the regulator of imprinted sites.
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.
Ghochikyan
Anahit
A
Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA 92647, USA.
Mkrtichyan
Mikayel
M
Loukinov
Dmitri
D
Mamikonyan
Gregory
G
Pack
Svetlana D
SD
Movsesyan
Nina
N
Ichim
Thomas E
TE
Cribbs
David H
DH
Lobanenkov
Victor V
VV
Agadjanyan
Michael G
MG
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000917:Antibody Formation; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D015704:CD4 Antigens / Q000032:analysis; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007114:Immunization; D018664:Interleukin-12 / Q000235:genetics; D020382:Interleukin-18 / Q000235:genetics; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D010957:Plasmids / Q000235:genetics; D017384:Sequence Deletion; D013737:Testis / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D015704:CD4 Antigens; D019496:Cancer Vaccines; C499208:Ctcfl protein, mouse; D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; D020382:Interleukin-18; D019444:Vaccines, DNA; D018664:Interleukin-12