Multiple myeloma induces Mcl-1 expression and survival of myeloid-derived suppressor cells

Abstract

Myeloid-derived suppressor cells (MDSC) are contributing to an immunosuppressive environment by their ability to inhibit T cell activity and thereby promoting cancer progression. An important feature of the incurable plasma cell malignancy Multiple Myeloma (MM) is immune dysfunction. MDSC were previously identified to be present and active in MM patients, however little is known about the MDSC-inducing and -activating capacity of MM cells. In this study we investigated the effects of the tumor microenvironment on MDSC survival. During MM progression in the 5TMM mouse model, accumulation of MDSC in the bone marrow was observed in early stages of disease development, while circulating myeloid cells were increased at later stages of disease. Interestingly, in vivo MDSC targeting by anti-GR1 antibodies and 5-Fluorouracil resulted in a significant reduced tumor load in 5TMM-diseased mice. In vitro generation of MDSC was demonstrated by increased T cell immunosuppressive capacity and MDSC survival was observed in the presence of MM-conditioned medium. Finally, increased Mcl-1 expression was identified as underlying mechanism for MDSC survival. In conclusion, our data demonstrate that soluble factors from MM cells are able to generate MDSC through Mcl-1 upregulation and this cell population can be considered as a possible target in MM disease.

Granulocytic myeloid-derived suppressor cells promote angiogenesis in the context of multiple myeloma

“…In contrast to these findings, soluble factors secreted by MM cells increased the viability of both MDSC subsets, especially PMN-MDSCs, in vitro . Similar observations were made by De Veirman et al who showed that conditioned medium from 5T33MM cells increased the viability of total MDSCs [19]. …”

“…Our results suggest that PMN-MDSCs could be mobilized from the BM into peripheral blood in the 5TGM1 model, whereas in the MOPC315.BM model these cells remain inside the BM. A recent report showed similar data, with a transient MO-MDSC expansion and a final increase in PMN-MDSCs (end-stage disease) in peripheral blood of C57BL/ KaLwRij mice bearing the 5TGM1-parental 5T33 myeloma [19]. However, in our study some intermediate time points included a relatively small number of animals (N=4) and need confirmation in future studies.…”

“…Within the BM of 5TGM1-bearing mice that were treated with anti-Gr1 antibody, De Veirman et al described reduced levels of MDSCs, with a preferential depletion of PMN-MDSCs, leading to a reduced tumor load in the BM of these mice [19]. As a preferential depletion of the granulocytic MDSC fraction has been shown in the BM of these mice, we analyzed the microvessel density (MVD) in BM sections from these mice and found that it was significantly lower in the anti-Gr1-treated 5TGM1-bearing mice compared to vehicle-treated 5TGM1-bearing mice, i.e.…”

“…Targeting of total MDSCs using anti-Gr1 antibodies or 5-fluorouracil in the murine 5TGM1 or 5T33MM models, respectively, showed promising results with a significant reduction of MM burden [19]. However, insight into the mechanisms by which this occurs is lacking and a direct effect of these strategies on myeloma cells should be investigated.…”

Signal transducer and activator of transcription 3 in myeloid-derived suppressor cells: an opportunity for cancer therapy

“…This is further supported by the observation that STAT3 prolongs the binding of C/EBPβ on the myc promoter [76]. Besides myc, other cell survival and cell cycle regulating proteins like Bcl-xL, survivin, Mcl-1 and cyclin D1 are upregulated by STAT3 [6], [31], [80]. STAT3 was further linked to proteins like S100A [81] and protein kinase C βII [82], which inhibit DC differentiation from myeloid progenitor cells and thereby promote MDSC accumulation.…”