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Induction of T cell-mediated immunity using a c-Myb DNA vaccine in a mouse model of colon cancer

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Abstract

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.

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Acknowledgments

The authors acknowledge and thank the following people for their expert critical input and technical assistance without whom this work would have not been possible; Sally Lightowler, Dr. Jordane Malaterre, Seb Dworkin, Dani Cardozo, Kym Stanley, Mira Liu, Carol Van Puyenbroek, Ralph Rossi, Dr. Jeremy Swann and Duy Huynh. The National Health and Medical Research Council have supported this work and RGR and PKD are the recipients of NHMRC Research Fellowships from this organization.

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Authors and Affiliations

  1. Pathology Department, The University of Melbourne, Melbourne, Australia

    Benjamin B. Williams, Meg Wall, Rebecca Yu Miao, Michael H. Kershaw, Phillip K. Darcy & Robert G. Ramsay

  2. Australian Stem Cell Centre, Melbourne, Australia

    Brenda Williams & Ivan Bertoncello

  3. Department of Pharmacology, Monash University, Melbourne, Australia

    Theo Mantamadiotis

  4. Children’s Cancer Institute Australia for Medical Research, Sydney, Australia

    Michelle Haber & Murray D. Norris

  5. Progen Pharmaceuticals Limited, Darra Queensland, Australia

    Anand Gautam

  6. Differentiation and Transcription Laboratory, Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, St Andrews Pl, East Melbourne, VIC, 3002, Australia

    Benjamin B. Williams, Meg Wall, Rebecca Yu Miao, Michael H. Kershaw, Phillip K. Darcy & Robert G. Ramsay

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  1. Benjamin B. Williams
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  2. Meg Wall
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  3. Rebecca Yu Miao
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  4. Brenda Williams
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  5. Ivan Bertoncello
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  11. Phillip K. Darcy
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Correspondence to Robert G. Ramsay.

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Phillip K. Darcy and Robert G. Ramsay contributed equally as senior authors.

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Williams, B.B., Wall, M., Miao, R.Y. et al. Induction of T cell-mediated immunity using a c-Myb DNA vaccine in a mouse model of colon cancer. Cancer Immunol Immunother 57, 1635–1645 (2008). https://doi.org/10.1007/s00262-008-0497-2

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  • DOI: https://doi.org/10.1007/s00262-008-0497-2

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