Development of anti-PAX3 immune responses; a target for cancer immunotherapy.
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.
Himoudi
Nourredine
N
Unit of Molecular Haematology and Cancer Biology, Institute of Child Health, London, WC1N 1EH, UK.
Nabarro
Steven
S
Yan
Mengyong
M
Gilmour
Kimberly
K
Thrasher
Adrian J
AJ
Anderson
John
J
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
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