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

Marilène Binsfeld,Jo Caers,Roy Heusschen,Virginie Lamour,Els Van Valckenborgh,Joséphine Muller,Frédéric Baron,Kim De Veirman,Hendrik De Raeve,Akeila Bellahcène,Yves Beguin

doi:10.18632/oncotarget.9270

Marilène Binsfeld, Jo Caers + Show 9 more

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https://doi.org/10.18632/oncotarget.9270

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Abstract

Multiple myeloma (MM) is a plasma cell malignancy characterized by the accumulation of tumor cells in the bone marrow (BM) and is associated with immunosuppression, angiogenesis and osteolysis. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature, immunosuppressive myeloid cells that promote tumor progression through different mechanisms.In this work, we studied the contribution of MDSC subsets to different disease-promoting aspects in MM. We observed an expansion of polymorphonuclear/granulocytic (PMN-)MDSCs in two immunocompetent murine MM models, while this was not observed for monocytic (MO-)MDSCs. Both MDSC subpopulations from MM-bearing mice were immunosuppressive, but PMN-MDSCs displayed a higher suppressive potential. Soluble factors secreted by MM cells increased the viability of MDSCs, whereas the presence of MDSCs did not affect the proliferation of MM cells in vitro or in vivo. Interestingly, we observed a pro-angiogenic effect of PMN-MDSCs in the context of MM using the chick chorioallantoic membrane assay. Consistently, MM-derived PMN-MDSCs showed an up-regulation of angiogenesis-related factors and reduced PMN-MDSC levels were associated with less angiogenesis in vivo. Finally, we identified MO-MDSCs as osteoclast precursors.These results suggest that MDSC subpopulations play diverging roles in MM. We show for the first time that PMN-MDSCs exert a pro-angiogenic role in MM.

Highlights

The plasma cell malignancy multiple myeloma (MM) is the second most frequent hematological malignancy and is characterized by the accumulation of monoclonal tumor cells in the bone marrow (BM)
In the BM, a significant decrease in percentages of polymorphonuclear/ granulocytic (PMN-)Myeloid-derived suppressor cells (MDSCs) and a trend towards decreased MO-MDSC levels was noted in the 5TGM1 model, whereas increased PMN-MDSC levels were observed in the MOPC315.BM model along with MM development (Figure 1A and 1B)
Higher levels of both MDSC populations were observed in the BM of naive C57BL/KaLwRij mice compared to naive Balb/c mice, and the opposite was observed in peripheral blood

Summary

Introduction

The plasma cell malignancy multiple myeloma (MM) is the second most frequent hematological malignancy and is characterized by the accumulation of monoclonal tumor cells in the bone marrow (BM). MM progression is facilitated by several disease-associated mechanisms, including angiogenesis [2] and immunosuppression [3]. MDSCs have been shown to accumulate in several pathological conditions including cancer. In mice, they are characterized by the co-expression of the CD11b and Gr1 surface molecules [4]. PMN-MDSCs present a CD11b+Ly6G+Ly6Cint phenotype, whereas MO-MDSCs are CD11b+Ly6G-Ly6Chigh. Both PMN- and MO-MDSCs suppress antigen-specific T-cell responses, even though they use different mechanisms [5, 6]. MDSCs contribute to tumor progression by suppressing immune responses, and by promoting tumor invasion and metastasis as well as tumor angiogenesis [7]

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