TY - JOUR
T1 - Dickkopf-1 (DKK1) is a widely expressed and potent tumor-associated antigen in multiple myeloma
AU - Qian, Jianfei
AU - Xie, Jin
AU - Hong, Sungyoul
AU - Yang, Jing
AU - Zhang, Liang
AU - Han, Xiaohong
AU - Wang, Michael
AU - Zhan, Fenghuang
AU - Shaughnessy, John D.
AU - Epstein, Joshua
AU - Kwak, Larry W.
AU - Yi, Qing
PY - 2007/9/1
Y1 - 2007/9/1
N2 - 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 peptide-tetramers, 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.
AB - 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 peptide-tetramers, 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.
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U2 - 10.1182/blood-2007-03-082529
DO - 10.1182/blood-2007-03-082529
M3 - Article
C2 - 17515399
AN - SCOPUS:34548828781
VL - 110
SP - 1587
EP - 1594
JO - Blood
JF - Blood
SN - 0006-4971
IS - 5
ER -