title: Identification of human leucocyte antigen (HLA)-A*0201-restricted cytotoxic T lymphocyte epitopes derived from HLA-DOβ as a novel target for multiple myeloma.
abstract: Despite the recent development of effective therapeutic agents against multiple myeloma (MM), new therapeutic approaches, including immunotherapies, remain to be developed. Here we identified novel human leucocyte antigen (HLA)-A*0201 (HLA-A2)-restricted cytotoxic T lymphocyte (CTL) epitopes from a B cell specific molecule HLA-DOβ (DOB) as a potential target for MM. By DNA microarray analysis, the HLA-DOB expression in MM cells was significantly higher than that in normal plasma cells. Twenty-five peptides were predicted to bind to HLA-A2 from the amino acid sequence of HLA-DOB. When screened for the immunogenicity in HLA-A2-transgenic mice immunized with HLA-DOB cDNA, 4 peptides were substantially immunogenic. By mass spectrometry analysis of peptides eluted from HLA-A2-immunoprecipitates of MM cell lines, only two epitopes, HLA-DOB232-240 (FLLGLIFLL) and HLA-DOB185-193 (VMLEMTPEL), were confirmed for their physical presence on cell surface. When healthy donor blood was repeatedly stimulated in vitro with these two peptides and assessed by antigen-specific γ-interferon secretion, HLA-DOB232-240 was more immunogenic than HLA-DOB185-193 . Additionally, the HLA-DOB232-240 -specific CTLs, but not the HLA-DOB185-193 -specific CTLs, displayed an major histocompatibility complex class I-restricted reactivity against MM cell lines expressing both HLA-A2 and HLA-DOB. Taken together, based on the physical presence on tumour cell surface and high immunogenicity, HLA-DOB232-240 might be useful for developing a novel immunotherapy against MM.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Cancer Vaccine Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Department of Biomedical Science, Jungwon University, Chungcheongbuk-do, South Korea.
authors.forename: Yoon Joong
authors.initials: YJ
authors.lastname: Kang
authors.forename: Wanyong
authors.initials: W
authors.lastname: Zeng
authors.forename: Weihua
authors.initials: W
authors.lastname: Song
authors.forename: Bruce
authors.initials: B
authors.lastname: Reinhold
authors.forename: Jaewon
authors.initials: J
authors.lastname: Choi
authors.forename: Vladimir
authors.initials: V
authors.lastname: Brusic
authors.forename: Takuto
authors.initials: T
authors.lastname: Yamashita
authors.forename: Aditya
authors.initials: A
authors.lastname: Munshi
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: Stephane
authors.initials: S
authors.lastname: Minvielle
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Nikhil
authors.initials: N
authors.lastname: Munshi
authors.forename: Ellis L
authors.initials: EL
authors.lastname: Reinherz
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Sasada
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003602:Cytotoxicity, Immunologic; D018076:DNA, Complementary / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005802:Genes, MHC Class II; D015789:HLA-A2 Antigen / Q000276:immunology*; D006681:HLA-D Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization; D007167:Immunotherapy / Q000379:methods*; D059425:Interferon-gamma Release Tests; D020014:K562 Cells; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy / Q000379:methods*; D009101:Multiple Myeloma / Q000276:immunology / Q000628:therapy*; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D019444:Vaccines, DNA / Q000276:immunology
chemical_list: D018076:DNA, Complementary; D018984:Epitopes, T-Lymphocyte; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D006681:HLA-D Antigens; C046148:HLA-DO antigens; D010446:Peptide Fragments; D019444:Vaccines, DNA
keywords: DNA microarray; HLA-DOβ; T cell epitope; cytotoxic T lymphocyte; multiple myeloma
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