TY - JOUR
T1 - Identification of an immunogenic DKK1 long peptide for immunotherapy of human multiple myeloma
AU - Li, Rong
AU - Zheng, Chengyun
AU - Wang, Qiang
AU - Bi, Enguang
AU - Yang, Maojie
AU - Hou, Jian
AU - Fu, Weijun
AU - Yi, Qing
AU - Qian, Jianfei
N1 - Publisher Copyright:
©2021 Ferrata Storti Foundation
PY - 2021/3/1
Y1 - 2021/3/1
N2 - Dickkopf-1 (DKK1), broadly expressed by tumor cells from human multiple myeloma (MM) and other cancers but absent from most normal tissues, may be an ideal target for immunotherapy. Our previous studies have shown that DKK1 (peptide)-specific cytotoxic T lymphocytes can effectively lyse primary MM cells in vitro. To develop DKK1-based vaccines that can be easily and inexpensively made and used by all patients, we identified a DKK1 long peptide (LP), DKK13-76-LP, that contains 74 amino acids and epitopes that can potentially bind to all major MHC class I and II molecules. Using HLA-A*0201- and HLA-DR*4-transgenic mouse models, we found that DKK1-specific CD4+ and CD8+ T-cell responses, detected by DKK1 short peptide (P20 and P66v)-HLA-A*0201 tetramer staining and cytotoxic assay for CD8+ T cells or by carboxyfluorescein diacetate succinimidyl ester (CSFE) dilution and IFN-g secretion for CD4+ T cells, respectively, can be induced in vivo by immunizing mice with the DKK13-76-LP. In addition, DKK13-76-LP also induced anti-DKK1 humoral immunity in the transgenic mice and the DKK1 antibodies were functional. Finally, DKK13-76-LP stimulated human blood T cells ex vivo to generate DKK1-specific CD4+ and CD8+ T-cell responses from 8 out of 10 MM patients with different MHC backgrounds. The generated DKK1-specific CD8+ cells efficiently lysed autologous MM cells from these patients. Thus, these results confirm the immunogenicity of the DKK13-76-LP in eliciting DKK1-specific CD4+ and CD8+ T-cell responses in vitro and in vivo, and suggest that the DKK13-76-LP can be used for immunotherapy of MM and other cancers.
AB - Dickkopf-1 (DKK1), broadly expressed by tumor cells from human multiple myeloma (MM) and other cancers but absent from most normal tissues, may be an ideal target for immunotherapy. Our previous studies have shown that DKK1 (peptide)-specific cytotoxic T lymphocytes can effectively lyse primary MM cells in vitro. To develop DKK1-based vaccines that can be easily and inexpensively made and used by all patients, we identified a DKK1 long peptide (LP), DKK13-76-LP, that contains 74 amino acids and epitopes that can potentially bind to all major MHC class I and II molecules. Using HLA-A*0201- and HLA-DR*4-transgenic mouse models, we found that DKK1-specific CD4+ and CD8+ T-cell responses, detected by DKK1 short peptide (P20 and P66v)-HLA-A*0201 tetramer staining and cytotoxic assay for CD8+ T cells or by carboxyfluorescein diacetate succinimidyl ester (CSFE) dilution and IFN-g secretion for CD4+ T cells, respectively, can be induced in vivo by immunizing mice with the DKK13-76-LP. In addition, DKK13-76-LP also induced anti-DKK1 humoral immunity in the transgenic mice and the DKK1 antibodies were functional. Finally, DKK13-76-LP stimulated human blood T cells ex vivo to generate DKK1-specific CD4+ and CD8+ T-cell responses from 8 out of 10 MM patients with different MHC backgrounds. The generated DKK1-specific CD8+ cells efficiently lysed autologous MM cells from these patients. Thus, these results confirm the immunogenicity of the DKK13-76-LP in eliciting DKK1-specific CD4+ and CD8+ T-cell responses in vitro and in vivo, and suggest that the DKK13-76-LP can be used for immunotherapy of MM and other cancers.
KW - Animals
KW - CD4-Positive T-Lymphocytes
KW - CD8-Positive T-Lymphocytes
KW - Epitopes, T-Lymphocyte
KW - Humans
KW - Immunotherapy
KW - Intercellular Signaling Peptides and Proteins
KW - Mice
KW - Multiple Myeloma/therapy
KW - Peptides
KW - T-Lymphocytes, Cytotoxic
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UR - http://www.scopus.com/inward/citedby.url?scp=85098770181&partnerID=8YFLogxK
U2 - 10.3324/haematol.2019.236836
DO - 10.3324/haematol.2019.236836
M3 - Article
C2 - 32079700
AN - SCOPUS:85098770181
SN - 0390-6078
VL - 106
SP - 838
EP - 846
JO - Haematologica
JF - Haematologica
IS - 3
ER -