The growing link between multiple myeloma and myeloid derived suppressor cells

In the last decade, many advances in the understanding of the molecular biology and pathogenesis of multiple myeloma (MM) have been made through study of the bone marrow (BM) [1]. The BM niche contains not only the malignant plasma cells but also the marrow microenvironment, which includes a cellular component of osteoclasts, osteoblasts, endothelial and immune cells, as well as the extracellular matrix, adhesion molecules and cytokines, and all may interact and play a part in promoting myeloma development [1]. The improved understanding of the “myeloma milieu” has generated a number of novel agents, such as the proteasome inhibitors and immune-modulatory drugs (Imids), which do not have a direct genotoxic effect on the malignant cells but act on the microenvironment. These “biological drugs” have been shown to be efficacious in MM and have resulted in improvement in the quality of life of patients and even in overall survival [2].

Another important development in the understanding of the biology of plasma cell dyscrasias relates to the recognition that MM is consistently preceded by a precursor state: monoclonal gammopathy of undetermined significance [MGUS] [3]. This preclinical state is also characterized by molecular and genetic features that are similar to those identified in MM [4], are genetically complex and probably develop from a multiple “hit” pathogenic process [5]. Despite all these significant advances, one should still bear in mind that MM remains an incurable disease, and that there are still some missing links in the chain of understanding of disease progression, and resistance to therapy.

One of the possible candidates for a major role in myelomagenesis and disease progression is the immune-suppressive population: myeloid derived suppressor cells (MDSCs) [6]. This subpopulation, derived from undifferentiated myeloid cells, achieves its immune-suppressive effects through multiple pathways [7], and in humans has been shown to mature into monocytic or granulocytic subpopulations [8]. The first link between MM and MDSCs relates to their immune-suppressive activity, which induces an impaired T-cell response mostly via the secretion of arginase-I and nitric oxide [9]. This immune-suppressive state generated by MDSCs is driven by a combined synergistic effect with other immune regulatory cells, such as T-regulatory cells (T-regs) [10], which is evident in the BM niche as well as the peripheral blood, and is associated with an increased number and a higher proportion of these cells in the above compartments [11].

It is now recognized that this subpopulation of cells not only generate their effect through immune-suppressive activity but also have plasticity in terms of differentiation. This constitutes the second link between MDSCs and MM, which relates to the intrinsic capacity of these cells to differentiate and transform into activated osteoclasts within the “myeloma environment,” thereby contributing to the progression of myeloma bone disease [12,13] and widening the vicious circle between osteoclasts and myeloma cells, which eventually results in an increased myeloma tumor burden.

In this issue of Leukemia and Lymphoma, Favaloro et al. add some novel data regarding the third possible link, which helps tighten the knot between myeloma and MDSCs [14]. They take advantage of the fact that MM is a unique disease model to study the effect of granulocyte colony stimulating factor (G-CSF) on MDSCs, because G-CSF is being used routinely for stem cell mobilization as the standard treatment of care for fit patients undergoing autologous stem cell transplant (ASCT). In this study they examined the number of MDSCs in the harvested graft collected after injection of G-CSF. They were able to demonstrate that G-CSF administered to induce stem cell mobilization caused an increase in the number of MDSCs in the peripheral blood of patients with MM [14].

This is in agreement with other reports [15] which identified that G-CSF used for stem cell mobilization expanded donor myeloid cells with the typical phenotype of MDSCs [15]. Based on these results, the authors also raise important questions regarding the number and percentage of these cells in the collected stem cell harvest, and more importantly, focus on their functional effect on lymphocyte reconstitution after transplant [14]. These issues relating to this specialized cell compartment will need to be reconsidered and further evaluated in future studies on transplant.

The last but not least important link between MM and MDSCs remaining to be considered relates to the observations of Favaloro et al. on the correlation between the number of MDSCs present and disease status [14]. They showed that in patients with quiescent asymptomatic disease such as MGUS or stable myeloma, the number of MDSCs is similar to that of age-matched controls, while in cases with active and progressive MM they expand [14]. Thus, evaluation of their presence in the peripheral blood or BM may be used as yet another surrogate marker for disease activity in MM.

In conclusion, targeting future therapy against this subpopulation of MDSCs may be used more effectively during active stages of disease, and could contribute to inhibiting myeloma progression through several interactive mechanisms.

Potential conflict of interest:

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