title: Dominant responses with conservation of T-cell receptor usage in the CD8+ T-cell recognition of a cancer testis antigen peptide presented through HLA-Cw7 in patients with multiple myeloma.
abstract: Cancer testis antigens exhibit physiological expression within germ cells and are frequently expressed in malignant tissue. Interestingly, immunological tolerance to cancer testis proteins does not appear to be established, and the expression of CTAg proteins within malignant cells can therefore lead to induction of cellular and humoral immunity. A considerable body of evidence now indicates that CD8-specific immunity plays an important role in the control of cancer cell growth, and a number of vaccine studies are in progress to boost CTAg-specific cellular immune responses. We have previously identified CTAg-specific immune responses in patients with multiple myeloma and reported that recognition of the MAGE-A1(289-298) peptide, which is described as being restricted by HLA-B*0702, was the most frequent response seen with our peptide panel. Here, we studied seven CD8+ T-cell clones specific for this peptide which were isolated from three patients with myeloma at several time-points. The affinity of peptide recognition was high with 50% maximal interferon-γ production observed at a peptide concentration of 10(-10) M and variation of only one order of magnitude between the affinities of the clones. Importantly, all the clones were able to recognise and kill multiple myeloma cell lines. Interestingly, one patient did not express HLA-B*0702, but three clones from this patient recognised the MAGE-A1(289-298) peptide on a lymphoblastoid cell line (LCLs) expressing HLA-Cw7, and we now show evidence that the MAGE-A1(289-298) peptide is expressed and recognised through Cw7. The T-cell receptor gene usage was determined in five clones and showed conserved features in both the α and the β chain genes indicating correlation between T-cell receptor usage and peptide specificity of cancer testis antigen-specific T-cell clones.
authors.affiliation: School of Cancer Studies, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, UK. GoodyeOC@bham.ac.uk
authors.forename: Oliver C
authors.initials: OC
authors.lastname: Goodyear
authors.forename: Hayden
authors.initials: H
authors.lastname: Pearce
authors.forename: Guy
authors.initials: G
authors.lastname: Pratt
authors.forename: Paul
authors.initials: P
authors.lastname: Moss
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D015236:HLA-C Antigens / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D058950:Melanoma-Specific Antigens / Q000276:immunology; D009101:Multiple Myeloma / Q000276:immunology*; D010455:Peptides / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D015236:HLA-C Antigens; C040178:HLA-C*70 antigen; C072011:MAGEA1 protein, human; D058950:Melanoma-Specific Antigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell