Decitabine shows potent anti-myeloma activity by depleting monocytic myeloid-derived suppressor cells in the myeloma microenvironment
Multiple myeloma (MM) remains incurable. The MM microenvironment supports MM cells’ survival and immune escape. Because myeloid-derived suppressor cells (MDSCs) is important in the MM microenvironment, and demethylating agent decitabine (DAC) can deplete MDSCs in vitro and in vivo, we hypothesized that DAC treatment could inhibit MM by depleting MDSCs in the MM microenvironment.
In this study, we used the mouse IL6 secreting, myeloma cell line MPC11 as a model. MDSCs were sorted using magnetic beads and cultured. A transwell coculture assay was used to mimic the microenvironment in vitro. And MPC11-bearing mice model was used to observe the efficacy of DAC treatment in vivo.
In vitro coculture assay indicated that MPC11 cells showed significantly lower proliferation rate, less IL6 production and more apoptosis when they were cocultured with bone marrow cells without MDSCs (nonMDSCs) or DAC-treated bone marrow cells (DAC BMs) than with MDSCs or PBS-treated bone marrow cells (CTR BM). Supplementation with M-MDSCs rescued the inhibitory effect of DAC BMs, while additional NOHA supplementation further antagonized the rescue effect of M-MDSCs. In MPC11-bearing mice, the combined treatment of DAC with anti-Gr1 antibody showed synergistic effect on inhibiting tumor growth and promoting T cell infiltration in the tumor tissue. M-MDSC reinfusion also antagonized the efficacy of DAC treatment.
DAC treatment can inhibit myeloma cell proliferation and induce enhanced autologous T cell immune response by depleting M-MDSCs in the MM microenvironment. We believe that DAC treatment could improve the prognosis of MM in future.
KeywordsDecitabine Myeloid-derived suppressor cells Myeloma Microenvironment
Myeloid-derived suppressor cells
Monocytic myeloid-derived suppressor cells
Granulocytic myeloid-derived suppressor cells
Bone marrow cells without MDSC
- Tc cells
Cytotoxic T cells
- Th cells
Helper T cells
This work was supported by the National Natural Science Foundation of China (No. 81600168 and 81702082), the Basic Research Project of Shenzhen Science and Technology Program (No. JCYJ20160422145031770), and the Sanming Project of Medicine in Shenzhen (No. SZSM201512006). We thank Yushi Yao from McMaster Immunology Research Centre, McMaster University (Hamilton, Ontario, Canada) for the helpful discussion and technical support.
This work was supported by the National Natural Science Foundation of China (Nos. 81600168 and 81702082), the Basic Research Project of Shenzhen Science and Technology Program (No. JCYJ20160422145031770), and the Sanming Project of Medicine in Shenzhen (No. SZSM201512006).
Compliance with ethical standards
Conflict of interest
Author Jihao Zhou declares that he has no conflict of interest. Author Qi Shen declares that he has no conflict of interest. Author Haiqing Lin declares that he has no conflict of interest. Author Lina Hu declares that he has no conflict of interest. Author Guoqiang Li declares that he has no conflict of interest. Author Xinyou Zhang declares that he has no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.
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