Identification of a new HLA-A2-restricted T-cell epitope within HM1.24 as immunotherapy target for multiple myeloma. - Archive ouverte HAL Access content directly
Journal Articles Experimental Hematology Year : 2006

Identification of a new HLA-A2-restricted T-cell epitope within HM1.24 as immunotherapy target for multiple myeloma.

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Abstract

OBJECTIVE: The aim of this study was identification of human leukocyte antigen (HLA)-A2-restricted T-cell epitopes within the HM1.24 antigen as target for multiple myeloma (MM)-directed specific peptide-based immunotherapy. METHODS: The HM1.24 sequence was scanned for immunogenic peptides using the HLA-binding prediction software SYFPEITHI and BIMAS. Peripheral blood mononuclear cells from HLA-A2(+) healthy volunteers/blood donors (ND) were stimulated with autologous HM1.24-peptide-loaded dendritic cells, and expanded in vitro. Activation of T cells was assessed by ELISpot and cytotoxicity by (51)Chromium ((51)Cr)-release assays. T2-cells pulsed with irrelevant peptide, the HM1.24(-)/HLA-A2(+) breast carcinoma cell line MCF-7 and the HM1.24(+)/HLA-A2(-) myeloma cell line RPMI-8226 were used as controls. Expression of the HM1.24 gene (BST2) was assessed using purified plasma cells and Affymetrix-U133A+B microarrays. Frequency of peptide-specific CD8(+) T cells was detected using the flow-cytometric tetramer technique. RESULTS: Of eight nona-peptides with the highest probability of binding to HLA-A2, the HM1.24 aa22-30 peptide (LLLGIGILV) showed the most frequent activation of CD8(+) T cells in healthy volunteers (specific activation in 8 of 11 [73%] ND; compared with 5-19% for the 7 other HM1.24 peptides). Antigen recognition by the HM1.24 aa22-30-specific CD8(+) T cells was HLA-A2-restricted (ELISpot with HLA-A2-blocking antibodies: median, 15; range, 14-18 spots/well; isotype-control antibodies: median, 47; range, 44-48). HM1.24-aa22-30-specific CD8(+) T cells lysed HLA-A2(+) myeloma-derived cell lines ((51)Cr-release assay: XG-1 vs MCF-7, 91% vs 0%; U266 vs MCF-7, 38% vs 4.2%; IM-9 vs RPMI-8226, 22% vs 0%). Using the cross-reactive Neisseria meningitidis peptide LLSLGIGILV-specific CD8(+) T cells recognizing target cells loaded with the HM1.24 aa22-30 peptide (LLLGIGILV) as well as the myeloma-derived cell line U266 could be expanded from MM patients. The HM1.24 gene was expressed at comparable levels by plasma cells from 65 MM patients, 7 patients with monoclonal gammopathy of undetermined significance, and 7 ND. CONCLUSIONS: HM1.24 aa22-30 is a newly identified HLA-A2-restricted T-cell epitope that is processed and presented by major histocompatibility complex class I. Specifically activated CD8(+) T cells are able to lyse MM cell lines. We conclude that HM1.24 aa22-30 represents a suitable candidate target for a specific peptide-based immunotherapy of MM.
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Dates and versions

inserm-00131759 , version 1 (21-02-2007)

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Michael Hundemer, Stefanie Schmidt, Maud Condomines, Alaviana Lupu, Dirk Hose, et al.. Identification of a new HLA-A2-restricted T-cell epitope within HM1.24 as immunotherapy target for multiple myeloma.. Experimental Hematology, 2006, 34 (4), pp.486-96. ⟨10.1016/j.exphem.2006.01.008⟩. ⟨inserm-00131759⟩
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