title: Active vaccination with Dickkopf-1 induces protective and therapeutic antitumor immunity in murine multiple myeloma.
abstract: Dickkopf-1 (DKK1), broadly expressed in myeloma cells but highly restricted in normal tissues, together with its functional roles as an osteoblast formation inhibitor, may be an ideal target for immunotherapy in myeloma. Our previous studies have shown that DKK1 (peptide)-specific CTLs can effectively lyse primary myeloma cells in vitro. The goal of this study was to examine whether DKK1 can be used as a tumor vaccine to elicit DKK1-specific immunity that can control myeloma growth or even eradicate established myeloma in vivo. We used DKK1-DNA vaccine in the murine MOPC-21 myeloma model, and the results clearly showed that active vaccination using the DKK1 vaccine not only was able to protect mice from developing myeloma, but it was also therapeutic against established myeloma. Furthermore, the addition of CpG as an adjuvant, or injection of B7H1-blocking or OX40-agonist Abs, further enhanced the therapeutic effects of the vaccine. Mechanistic studies revealed that DKK1 vaccine elicited a strong DKK1- and tumor-specific CD4+ and CD8+ immune responses, and treatment with B7H1 or OX40 Abs significantly reduced the numbers of IL-10-expressing and Foxp3+ regulatory T cells in vaccinated mice. Thus, our studies provide strong rationale for targeting DKK1 for immunotherapy of myeloma patients.
authors: Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors: Jianfei
authors: J
authors: Qian
authors: Yuhuan
authors: Y
authors: Zheng
authors: Chengyun
authors: C
authors: Zheng
authors: Lijuan
authors: L
authors: Wang
authors: Hong
authors: H
authors: Qin
authors: Sungyoul
authors: S
authors: Hong
authors: Haiyan
authors: H
authors: Li
authors: Yong
authors: Y
authors: Lu
authors: Jin
authors: J
authors: He
authors: Jing
authors: J
authors: Yang
authors: Sattva
authors: S
authors: Neelapu
authors: Larry W
authors: LW
authors: Kwak
authors: Jian
authors: J
authors: Hou
authors: Qing
authors: Q
authors: Yi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007167:Immunotherapy; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000276:immunology*; D016753:Interleukin-10 / Q000378:metabolism; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D053262:Receptors, OX40 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D014407:Tumor Cells, Cultured; D014611:Vaccination; D019444:Vaccines, DNA / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; C501127:Dkk1 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; D019444:Vaccines, DNA; D016753:Interleukin-10