Immune suppression in Multiple Myeloma induced by myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous mix of myeloid cells in different maturation stages generated in the BM. The role of MDSCs in cancer is to suppress T-cell responses, thereby likely regulating tumor progression. In mice, MDSCs are identified by expression of surface markers CD11b and Gr-1. The role of MDSCs in immune suppression in MM is not yet described. We investigated the immunosuppressive activity and mechanism of MDSC subsets in the syngeneic, immunocompetent 5TMM mouse model (5T2 and 5T33 models). CD11b+Ly6G-/low and CD11b+Ly6Ghi myeloid MDSC subsets were detected in 5TMM-diseased BM. These subsets were analyzed for T-cell suppressive activity. Both MDSC subsets from 5TMM BM were able to suppress antigen-specific T-cell responses at a higher level compared to purified MDSC subsets from normal BM. On average, Ly6G-/low MDSCs were more suppressive than Ly6Ghi MDSCs. To unravel the suppressive mechanism of MDSC subsets, inhibitors were used in ovalbumin-stimulated cocultures. Ly6G-/low MDSC-mediated suppression was partially reversed by the iNOS inhibitor L-NMMA and the COX-2 inhibitor sc-791, both of which lower the NO concentration in culture. In contrast, superoxide dismutase and especially catalase enhance NO concentrations, resulting in enhanced T-cell suppression. None of these inhibitors had any impact on the Ly6Ghi MDSC-mediated suppression. The Ly6G-/low population was further analysed and could be subdivided into 3 subpopulations based on the expression of Ly6C and SSC. These subpopulations show a different expression of surface markers, including SiglecF (eosinophil marker) and CD115/CCR2 (inflammatory monocyte markers). These subpopulations were sorted and analysed for their T-cell suppressive activity. Only the inflammatory monocytes have suppressive capacity. In conclusion, these data reveal the presence of MDSCs as a novel immune suppressive strategy employed by MM cells in the BM.