Induction of T cell-mediated immunity using a c-Myb DNA vaccine in a mouse model of colon cancer.
Overexpression of the proto-oncogene c-Myb occurs in more than 80% of colorectal cancer (CRC) and is associated with aggressive disease and poor prognosis. To test c-Myb as a therapeutic target in CRC we devised a DNA fusion vaccine to generate an anti-CRC immune response. c-Myb, like many tumor antigens, is weakly immunogenic as it is a "self" antigen and subject to tolerance. To break tolerance, a DNA fusion vaccine was generated comprising wild-type c-Myb cDNA flanked by two potent Th epitopes derived from tetanus toxin. Vaccination was performed targeting a highly aggressive, weakly immunogenic, subcutaneous, syngeneic, colon adenocarcinoma cell line MC38 which highly expresses c-Myb. Prophylactic intravenous vaccination significantly suppressed tumor growth, through the induction of anti-tumor immunity for which the tetanus epitopes were essential. Vaccination generated anti-tumor immunity mediated by both CD4+ and CD8+ T cells and increased infiltration of immune effector cells at the tumor site. Importantly, no evidence of autoimmune pathology in endogenous c-Myb expressing tissues was detected as a consequence of breaking tolerance. In summary, these results establish c-Myb as a potential antigen for immune targeting in CRC and serve to provide proof of principle for the continuing development of DNA vaccines targeting c-Myb to bring this approach to the clinic.
Williams
Benjamin B
BB
Pathology Department, The University of Melbourne, Melbourne, Australia. ben.williams@petermac.org
Wall
Meg
M
Miao
Rebecca Yu
RY
Williams
Brenda
B
Bertoncello
Ivan
I
Kershaw
Michael H
MH
Mantamadiotis
Theo
T
Haber
Michelle
M
Norris
Murray D
MD
Gautam
Anand
A
Darcy
Phillip K
PK
Ramsay
Robert G
RG
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000628:therapy; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005805:Genes, MHC Class I / Q000502:physiology; D020570:Genes, myb / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007109:Immunity; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D000090063:Proto-Oncogene Mas; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013744:Tetanus Toxin / Q000235:genetics / Q000276:immunology; D014407:Tumor Cells, Cultured; D014611:Vaccination; D019444:Vaccines, DNA / Q000627:therapeutic use*
D019496:Cancer Vaccines; C000715470:MAS1 protein, human; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D013744:Tetanus Toxin; D019444:Vaccines, DNA; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins