Abstract
Progression of multiple myeloma is regulated by factors intrinsic to the clonal plasma cells (PC) and by the immune effector cells in the tumor microenvironment. In this study, we investigated the interaction between CD304 expression on myeloid-derived suppressor cells (MDSC) and galectin-1 from malignant PCs in the context of autologous stem cell transplantation (ASCT) for multiple myeloma. Using high-throughput screening, CD304 expression on circulating monocytic MDSCs (M-MDSC; CD14+HLA-DRlow/-) was compared before and after ASCT. There was a significantly higher M-MDSC expression of CD304 before ASCT and a clear correlation between circulating pre-ASCT M-MDSC frequency and serum galectin-1 concentration. Treatment of pre-ASCT M-MDSCs, but not post-ASCT M-MDSCs, with galectin-1 in vitro expanded the M-MDSC population and increased expression of CD304. High galectin-1 expression by malignant PCs was associated with poor clinical outcomes. M-MDSC development and expression of CD304 were differentially induced when healthy donor peripheral blood mononuclear cells were cultured with the human multiple myeloma cell lines RPMI-8226 and JJN3, which express high and low galectin-1, respectively. Inhibition of galectin-1 reduced M-MDSC proliferation induced by RPMI-8226 cells but not by JJN3 cells, and blockade of CD304 reduced M-MDSC migration induced by RPMI-8226 cells but not by JJN3 cells. In addition, blockade of CD304 reversed suppression of the in vitro cytotoxic effect of melphalan by pre-ASCT M-MDSCs. Our data demonstrate that multiple myeloma-derived galectin-1 could mediate the tumor-promoting effect of M-MDSCs through its interaction with CD304 on M-MDSCs and contribute to multiple myeloma progression after ASCT.See related Spotlight on p. 488.