Decitabine shows potent anti-myeloma activity by depleting monocytic myeloid-derived suppressor cells in the myeloma microenvironment

Purpose 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. Methods 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. Results 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. Conclusions 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.