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Haematologica 2021 Volume 106(3):838-846
Cell Therapy and Immunotherapy
Identification of an immunogenic DKK1 long peptide for immunotherapy of human multiple myeloma
Rong Li,1,2,3 Chengyun Zheng,4 Qiang Wang,1° Enguang Bi,1° Maojie Yang,1° Jian Hou,5 Weijun Fu,2 Qing Yi1° and Jianfei Qian1°
1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, OH, USA; 2The Center of Lymphoma and Multiple Myeloma, ChangZheng Hospital, The Second Military Medical University, Shanghai, P. R. China; 3Navy Medical Center of PLA, Shanghai, P. R. China; 4Department of Hematology, Second Hospital of Shandong University, Jinan, P. R. China and 5Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
°Current address: Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, TX, USA
ABSTRACT
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 pre- vious studies have shown that DKK1 (peptide)-specific cytotoxic T lympho- cytes 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 cyto- toxic 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 stimu- latedhumanbloodTcellsexvivotogenerateDKK1-specificCD4+ andCD8+ T-cell responses from 8 out of 10 MM patients with different MHC back- grounds. The generated DKK1-specific CD8+ cells efficiently lysed autolo- gous MM cells from these patients. Thus, these results confirm the immuno- genicity of the DKK1 -LP in eliciting DKK1-specific CD4+ and CD8+ T-cell
immunotherapy of MM and other cancers.
Introduction
Dickkopf-1 (DKK1) is highly expressed in tumor cells of multiple myeloma (MM) and other cancer types,1,2 but is absent from normal tissues and organs, with the exception of the placenta and prostate.3,4 Our previous studies have shown that DKK1 (peptide)-specific cytotoxic T lymphocytes (CTL) can effectively lyse primary myelo- ma cells in vitro, confirming that DKK1 may be a good tumor-associated antigen. We explored the efficacy of a murine DKK1 DNA vaccine in the murine MOPC-21 myeloma model and showed that active vaccination using the DKK1 vaccine was not only able to protect mice from developing myeloma, but was also therapeutic against established myeloma. Mechanistic studies revealed that the DKK1 vaccine elicited strong DKK1- and tumor-specific CD4+ and CD8+ immune responses.5 Thus, our stud- ies provide a strong rationale for targeting DKK1 for immunotherapy in myeloma patients.
There has been substantial progress in the clinical use of long peptide (LP) thera- peutic vaccination in recent years.6,7 Melief et al. reported an LP vaccine encompassing
3-76
responses in vitro and in vivo, and suggest that the DKK13-76-LP can be used for
Correspondence:
RONG LI
lirong785@hotmail.com
CHENGYUN ZHENG
zhengchengyun186@126.com
JIANFEI QIAN
jqian2@houstonmethodist.org
Received: August 28, 2019. Accepted: February 12, 2020. Pre-published: February 20, 2020.
https://doi.org/10.3324/haematol.2019.236836
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