Dickkopf-1 (DKK1) is a widely expressed and potent tumor-associated antigen in multiple myeloma.
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.
Qian
Jianfei
J
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.
Xie
Jin
J
Hong
Sungyoul
S
Yang
Jing
J
Zhang
Liang
L
Han
Xiaohong
X
Wang
Michael
M
Zhan
Fenghuang
F
Shaughnessy
John D
JD
Epstein
Joshua
J
Kwak
Larry W
LW
Yi
Qing
Q
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
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