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Identification of an immunogenic DKK1 long peptide for immunotherapy of human multiple myeloma
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 c...
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Published in: | Haematologica (Roma) 2021-03, Vol.106 (3), p.838-846 |
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Main Authors: | , , , , , , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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. |
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ISSN: | 0390-6078 1592-8721 |
DOI: | 10.3324/haematol.2019.236836 |