title: Dickkopf-1 (DKK1) is a widely expressed and potent tumor-associated antigen in multiple myeloma.
abstract: The identification of novel tumor-associated antigens, especially those shared among patients, is urgently needed to improve the efficacy of immunotherapy for multiple myeloma (MM). In this study, we examined whether Dickkopf-1 (DKK1), a protein that is not expressed in most normal tissues but is expressed by tumor cells from almost all patients with myeloma, could be a good candidate. We identified and synthesized DKK1 peptides for human leukocyte antigen (HLA)-A*0201 and confirmed their immunogenicity by in vivo immunization in HLA-A*0201 transgenic mice. We detected, using peptidetetramers, low frequencies of DKK1 peptide-specific CD8-positive (CD8(+)) T cells in patients with myeloma and generated peptide-specific T-cell lines and clones from HLA-A*0201-positive (HLA-A*0201(+)) blood donors and patients with myeloma. These T cells efficiently lysed peptide-pulsed but not unpulsed T2 or autologous dendritic cells, DKK1-positive (DKK1(+))/HLA-A*0201(+) myeloma cell lines U266 and IM-9, and, more importantly, HLA-A*0201(+) primary myeloma cells from patients. No killing was observed on DKK1(+)/HLA-A*0201-negative (HLA-A*0201(-)) myeloma cell lines and primary myeloma cells or HLA-A*0201(+) normal lymphocytes, including B cells. These results indicate that these T cells were potent cytotoxic T cells and recognized DKK1 peptides naturally presented by myeloma cells in the context of HLA-A*0201 molecules. Hence, our study identifies DKK1 as a potentially important antigen for immunotherapy in MM.
authors.affiliation: Department of Lymphoma and Myeloma, Division of Cancer Medicine, and the Center for Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Qian
authors.forename: Jin
authors.initials: J
authors.lastname: Xie
authors.forename: Sungyoul
authors.initials: S
authors.lastname: Hong
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Han
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
authors.forename: Joshua
authors.initials: J
authors.lastname: Epstein
authors.forename: Larry W
authors.initials: LW
authors.lastname: Kwak
authors.forename: Qing
authors.initials: Q
authors.lastname: Yi
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D015234:HLA-A Antigens / Q000276:immunology*; D015789:HLA-A2 Antigen; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D020014:K562 Cells; D051379:Mice; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000276:immunology* / Q000628:therapy; D010455:Peptides / Q000276:immunology* / Q000494:pharmacology; D014611:Vaccination
chemical_list: D000951:Antigens, Neoplasm; C501126:DKK1 protein, human; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides