Abstract
PAX3 is overexpressed in several human cancers and is absent from normal adult human tissues. It is known to have an oncogenic function in human malignancy, and is therefore a promising target for cancer immunotherapy. We screened the murine and human PAX3 amino acid sequences for peptides that bind common MHC class I types, and identified murine GVFINGRPL and human KLTEARVQV sequences. Mice immunised with either a selected PAX3 peptide, or with a PAX3 expressing DNA vector, developed specific anti-PAX3 immune responses that inhibited tumour growth. The intensity of the immune response was significantly enhanced by pulsing of the peptide onto dendritic cells. Anti-PAX3 T cell lines were established from splenocytes of immunised mice. Intravenous administration of anti-PAX3 T cells caused regression of established tumours indicating a promising clinical application for anti-PAX3 immunotherapy. The human peptide stimulated growth of similar T cell lines from peripheral blood of three out of three normal human blood donors. These showed specific cytotoxicity against a range of human PAX3+ and HLA-A2+ cancer cell lines. Moreover, an anti-PAX3 response was detected as a component of the anti-tumour immune response in a patient treated with lysate pulsed dendritic cell vaccination. The ability to generate strong and specific anti PAX3 immune responses from the T cell repertoire in both mice and humans, provides evidence for PAX3 as a promising target for immunotherapy of cancer.
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Abbreviations
- 76-9-P3F:
-
PAX3-FKHR stably transfected into 76-9 cell line
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Acknowledgments
The authors have no conflicting financial interests. Thanks to Dr A Anderson for critical reading of the manuscript. Supported by grants from Cancer Research UK, SPARKS, Leukaemia Research Fund, Wellcome Trust and RICC.
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Himoudi, N., Nabarro, S., Yan, M. et al. Development of anti-PAX3 immune responses; a target for cancer immunotherapy. Cancer Immunol Immunother 56, 1381–1395 (2007). https://doi.org/10.1007/s00262-007-0294-3
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DOI: https://doi.org/10.1007/s00262-007-0294-3