title: Development of anti-PAX3 immune responses; a target for cancer immunotherapy.
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.
authors.affiliation: Unit of Molecular Haematology and Cancer Biology, Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Nourredine
authors.initials: N
authors.lastname: Himoudi
authors.forename: Steven
authors.initials: S
authors.lastname: Nabarro
authors.forename: Mengyong
authors.initials: M
authors.lastname: Yan
authors.forename: Kimberly
authors.initials: K
authors.lastname: Gilmour
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.forename: John
authors.initials: J
authors.lastname: Anderson
mesh_terms: D000293:Adolescent; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D000939:Epitopes / Q000276:immunology / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000276:immunology*; D010455:Peptides / Q000276:immunology* / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation
chemical_list: D019496:Cancer Vaccines; D000939:Epitopes; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D010455:Peptides; D012333:RNA, Messenger; C068686:Pax3 protein, mouse