Myeloma Cell-Derived Factors Retard the Differentiation and Function of Dendritic Cells.

Abstract

Multiple myeloma (MM) is a B-cell malignancy often associated with a suppressed immune system. The mechanisms for the immunosuppression are largely unknown. In this study, we examined, using the murine 5T33 myeloma model, the effects of tumor cell or its-derived factors on the differentiation and function of bone marrow-derived dendritic cells (BMDCs). Our results showed that differentiation of BMDCs was retarded in the presence of 10% of tumor-derived supernatant (TSN). This is evident by, compared with control cells, the downregulated expression of surface molecules including CD40, CD86 and MHC class II; secretion of higher levels of IL-10 and lower levels of IL-12; and a poor T-cell response in an allogeneic mixed lymphocyte reaction induced by TSN-treated cells. The same phenomenon was also observed when the bone marrow progenitor cells were cocultured, either in direct contact or separated by transwell membrane, with myeloma cells. The treatment downregulated the expression of phosphorylated extracellular signal-related kinase (ERK) and mitogen-induced extracellular kinase (MEK), and upregulated the expression of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and signal transducer and activator of transcription-3 (STAT3) in the cells. As a high level of interleukin (IL)-10, IL-6, vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-b can be detected in TSN, we examined whether these cytokines were responsible. Our results showed that addition of TGF-b, IL-10 and/or IL-6 could largely replace TSN in retarding the differentiation of BMDCs, and neutralizing antibodies against these cytokines, especially in combination, were able to block the effects of TSN or tumor cells on BMDCs. Finally, our results showed that inhibiting p38 MAPK or STAT3 restored the differentiation and function of these cells. Hence, our study not only sheds light on the mechanisms of tumor-induced immune evasion in MM and but also provides one of the solutions to overcome the problems.