Lack of effective T-lymphocyte response to the PAX3/FKHR translocation area in alveolar rhabdomyosarcoma

• Published in: Cancer Immunology, Immunotherapy Vol. 54; no. 6; pp. 526 - 534
• Main Authors: RODEBERG, David A, NUSS, Rebecca A, HEPPELMANN, Carrie J, CELIS, Esteban
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.06.2005; Springer Nature B.V
• Subjects: Algorithms; Amino Acid Sequence; Antigens; Antineoplastic agents; Biological and medical sciences; Cancer Vaccines - immunology; Cell Line; Chromosome aberrations; Cytotoxicity; Dendritic cells; Diseases of the osteoarticular system; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; Forkhead Box Protein O1; Forkhead Transcription Factors; HLA-A3 Antigen - immunology; Humans; Immunization; Immunotherapy; Lymphocytes; Medical genetics; Medical sciences; Molecular Sequence Data; Paired Box Transcription Factors; PAX3 Transcription Factor; Peptides; Pharmacology. Drug treatments; Proteins; Recombinant Fusion Proteins - immunology; Rhabdomyosarcoma, Alveolar - genetics; Rhabdomyosarcoma, Alveolar - immunology; T-Lymphocytes - immunology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Helper-Inducer - immunology; Transcription factors; Transcription Factors - genetics; Transcription Factors - immunology; Translocation, Genetic; Tumors; Tumors of striated muscle and skeleton; Vaccines; United States > US; Chromosomal aberration; Dendritic cell; Cancer vaccine; Peptides; Sarcoma; Cytotoxic T-lymphocyte; Helper cell; Vaccine; Malignant tumor; Helper T-lymphocyte; Striated muscle disease; Antigen presenting cell; Efficiency; T-Lymphocyte; Cytogenetics; Abnormal chromosome; Transcription factor FOXO1; Cytotoxic T lymphocyte; Peptide; Alveolar rhabdomyosarcoma; Chromosome translocation
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-004-0625-6

Alveolar rhabdomyosarcoma (ARMS) frequently contains the fusion transcription factor PAX3/FKHR. Therefore, clinical studies have been initiated to utilize the PAX3/FKHR translocation point area as a peptide vaccine against ARMS. Our study was directed at identifying antigenic T-lymphocyte epitopes at the PAX3/FKHR translocation point area. The peptide sequence surrounding the PAX3/FKHR translocation point was evaluated by MHC binding algorithms for potential T-lymphocyte antigenic epitopes (class I molecules HLA-A1, -A2 and -A3; class II molecules HLA-DR1, -DR4 and -DR7). Using in vitro techniques, dendritic cells loaded with PAX3/FKHR peptides were used to stimulate naive T-lymphocytes. T-lymphocyte activity was then evaluated by 51Cr release and 3H-thymidine uptake assays. Only one HLA-A3-restricted epitope was predicted by the algorithms. The peptide was prepared and tested for its ability to stimulate naive cytotoxic T-lymphocytes (CTLs). Unfortunately, the peptide was unsuccessful at stimulating naive CTL. However, induction of naive helper T-lymphocytes (HTL) to recognize and respond to the PAX3/FKHR translocation peptide was successful. Yet, this HTL peptide activity did not translate into recognition of PAX3/FKHR-containing ARMS tumor cells. It appears that the fusion area of PAX3/FKHR may not be a good source of antigenic anti-tumor peptide epitopes. These results raise serious concerns about the success and applicability of future peptide-based vaccine immunotherapy directed at the PAX3/FKHR translocation point.