Abstract
Granulocytic-Myeloid-derived suppressor cells (G-MDSC) are increased in Multiple Myeloma (MM) patients but the mechanisms of G-MDSC generation are still unknown. There are many evidences of the role of mesenchymal stem cells (MSC) in promoting MM cell growth, survival and drug-resistance. We here used a specific experimental model in vitro to evaluate the ability of MSC to induce G-MDSC. We found that although MSC derived from healthy donors (HD), MGUS and MM were able to generate the same amount of MDSC, only MM-MSC-educated G-MDSC exhibited suppressive ability. In addition, in comparison with MSC derived from HD, MM-MSC produce higher amount of immune-modulatory factors that could be involved in MDSC induction. Compared to G-MDSC obtained from co-culture models with MSC from healthy subjects, both MGUS and MM-MSC-educated G-MDSC showed increase of immune-modulatory factors. However, only MM-MSC educated G-MDSC 1) up-regulated immune-suppressive factors as ARG1 and TNFα, 2) expressed higher levels of PROK2, important in angiogenesis and inflammatory process, and 3) showed ability to digest bone matrix.Our data demonstrate that MM-MSC are functionally different from healthy subjects and MGUS-MSC, supporting an evolving concept regarding the contribution of MM-MSC to tumor development and progression.
Highlights
Monoclonal gammopathies encompasse a spectrum of clinical variants ranging from monoclonal gammopathy of uncertain significance (MGUS) through smoldering Multiple Myeloma (MM), up to the most aggressive, symptomatic MM and plasma cell leukemia [1, 2]
We incubated G-Myeloid-derived suppressor cells (MDSC) obtained from MM and healthy donors (HD) with autologous Carboxyfluorescein succinimidyl ester (CFSE)-labeled T cells and we found that only MM G-MDSC were able to reduce autologous T cells proliferation (44.3 ± 2.3% vs 30.0 ± 1.5%, p = 0.009) (Figure 1B)
To explore their influence in the induction of MDSC, peripheral blood mononucleated cells (PBMC) from healthy donors were co-cultured with HD, MGUS- or MM-mesenchymal stem cells (MSC) for one week
Summary
Monoclonal gammopathies encompasse a spectrum of clinical variants ranging from monoclonal gammopathy of uncertain significance (MGUS) through smoldering Multiple Myeloma (MM), up to the most aggressive, symptomatic MM and plasma cell leukemia [1, 2]. There are several evidences indicating that development of MM is due to uncontrolled proliferation of plasma cells (PC) and to change in the bone marrow (BM) microenvironment [3]. The host immune system has a pivotal role for the PC growth, proliferation, survival, migration and resistance to drugs and is responsible for some clinical manifestations of MM [4, 7, 8]. Myeloid-derived suppressor cells (MDSC) include myeloid cells at different stage of maturation characterized by the ability to suppress immune responses, including T www.impactjournals.com/oncotarget cell proliferation and cytokine production [9,10,11]. Several groups highlighted the emerging role of MDSC in MM pathogenesis and clinical behavior, and have documented their increase in both peripheral blood (PB) and BM of MM patients [4, 12,13,14,15,16,17,18]
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