Active vaccination with Dickkopf-1 induces protective and therapeutic antitumor immunity in murine multiple myeloma

ArticleinBlood 119(1):161-9 · November 2011with26 Reads
DOI: 10.1182/blood-2011-07-368472 · Source: PubMed
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.
    • "Interestingly, a therapeutic approach based on tumour vaccine therapy showed that stimulating autologous T cells from MM patients with DKK1 peptides as the immunogen was able to specifically target myeloma cells without affecting normal blood cells [84]. Active vaccination against DKK1 in mouse models of MM elicited a specific T cell response against MM cells and efficiently protected mice against myeloma [85]. This pre-clinical study provides a proof-of-concept that DKK1 vaccines could be used as a therapeutic approach against MM as well as for the prevention of recurrent MM. "
    [Show abstract] [Hide abstract] ABSTRACT: Dickkopf-1 (DKK1) is a secreted Wnt/β-catenin pathway antagonist involved in embryogenesis. It was first described 25 years ago for its function in head induction and limb morphogenesis. Since then, this protein has been widely studied in the context of active Wnt/β-catenin signalling during cellular differentiation and development. Dysregulation of DKK1 has been associated with bone pathologies and has now emerged as a potential biomarker of cancer progression and prognosis for several types of malignancies. Reducing the amount of circulating DKK1 may reveal a simple and efficient strategy to limit or reverse cancer growth. This review will provide an overview of the role of Dickkopf-1 in cancer and explore its potential use as a biomarker and therapeutic target.
    Full-text · Article · Jun 2016
    • "To study the role of the identified chemokines in MO and MΦ recruitment in vivo, we used the murine 5TGM1 MM model established in C57BL/KawRij mice [12]. Because the mouse does not have CCL14 homology and human CCL14 cDNA shares the highest similarity with human and mouse CCL3 (data not shown), we first examined in vitro murine MΦ chemotaxis in the presence of neutralizing antibodies to murine CCL3 or CCL2. "
    [Show abstract] [Hide abstract] ABSTRACT: We previously showed that macrophages (MΦs) infiltrate the bone marrow (BM) of patients with myeloma and may play a role in drug resistance. This study analyzed chemokines expressed by myeloma BM that are responsible for recruiting monocytes to the tumor bed. We found that chemokines CCL3, CCL14, and CCL2 were highly expressed by myeloma and BM cells, and the levels of CCL14 and CCL3 in myeloma BM positively correlated with the percentage of BM-infiltrating MΦs. In vitro, these chemokines were responsible for chemoattracting human monocytes to tumor sites and in vivo for MΦ infiltration into myeloma-bearing BM in the 5TGM1 mouse model. Surprisingly, we also found that these chemokines stimulated MΦ in vitro proliferation induced by myeloma cells and in vivo in a human myeloma xenograft SCID mouse model. The chemokines also activated normal MΦ polarization and differentiation into myeloma-associated MΦs. Western blot analysis revealed that these chemokines promoted growth and survival signaling in MΦs via activating the PI3K/Akt and ERK MAPK pathways and c-myc expression. Thus, this study provides novel insight into the mechanism of MΦ infiltration of BM and also potential targets for improving the efficacy of chemotherapy in myeloma.
    Full-text · Article · Jun 2015
    • "Moreover, the vaccine was able to protect mice from MM challenge and exhibited therapeutic effect against established MM [44]. Two anti-DKK1 neutralizing antibodies have been tested as therapeutic agents in mice bearing human primary MM. "
    [Show abstract] [Hide abstract] ABSTRACT: Multiple myeloma remains an incurable disease although the prognosis has been improved by novel therapeutics and agents recently. Relapse occurs in the majority of patients and becomes fatal finally. Immunotherapy might be a powerful intervention to maintain a long-lasting control of minimal residual disease or to even eradicate disseminated tumor cells. Several tumor-associated antigens have been identified in patients with multiple myeloma. These antigens are expressed in a tumor-specific or tumor-restricted pattern, are able to elicit immune response, and thus could serve as targets for immunotherapy. This review discusses immunogenic antigens with therapeutic potential for multiple myeloma.
    Full-text · Article · May 2012
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