Increased Level of both CD4+FOXP3+ Regulatory T Cells and CD14+HLA-DR−/low Myeloid-Derived Suppressor Cells and Decreased Level of Dendritic Cells in Patients with Multiple Myeloma

Abstract

Patients with multiple myeloma (MM) suffer from a general impaired immunity comprising deficiencies in humoral responses, T‐cell responses as well as dendritic cell (DC) function. Thus, to achieve control of tumour growth through immune therapy constitutes a challenge. Careful evaluation of the immune status in patients with MM seems crucial prior to active immune therapy. We evaluated the proportion of both, DC, Treg cells and myeloid‐derived suppressor cells (MDSC) in peripheral blood from patients with MM at diagnosis and in remission as well as patients with monoclonal gammopathy of undetermined significance (MGUS). We found that the proportion of both myeloid (m) DC and plasmacytoid (p) DC in patients at diagnosis was lowered compared to control donors, while only the proportion of pDC in patients in remission and with MGUS was significantly lower than in controls. The proportion of CD4+FOXP3+ Treg cells was increased in patients at diagnosis and not in patients in remission or with MGUS. Also, Treg cells from patients with MM were functionally intact as they were able to inhibit proliferation of both CD4 and CD8 T cells. Finally, we observed an increase in the proportion of CD14+HLA‐DR−/low MDSC in patients with MM at diagnosis, illustrating that this cell fraction is also distorted in patients with MM. Taken together, our results illustrate that, both mDC, pDC, Treg cells and MDSC are affected in patients with MM underlining the fact that the immune system is dysregulated as a consequence of the disease.

Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

“…Initially, a decrease in Treg numbers was reported in MM patients, along with a defect in their ability to suppress T-cell proliferation [57]. In contrast, several more recent studies have concluded that the number of functionally intact Treg is increased in MM patients [49,50,[58][59][60]. These observations are in accordance with observations made in several other malignancies [56], and suggest that MM cells evade immune surveillance partially through the increase of suppressive Tregs [60].…”

“…Both myeloid and plasmacytoid DCs and their precursors are decreased in MM patients [47][48][49][50]. In a first study, Brown et al reported that tumor-derived TGF-β1 and IL-10 inhibit the up-regulation of CD80 and CD86 co-stimulatory molecules on DCs from MM patients [40].…”

“…Although their phenotype in humans is not yet well-defined, they are generally delineated as CD11b + CD33 + HLA-DR − and comprise monocytic and granulocytic/neutrophil-like subpopulations [63]. An increase of MDSCs in peripheral blood and bone marrow of MM patients has been observed [49,64,65]. Moreover, MDSCs induce MM growth and suppress T-cell mediated immune responses, while MM cells induce MDSC development, resulting in a bidirectional interaction [64].…”

Myeloid Derived Suppressor Cells and Their Role in Diseases

“…[23,24]. Several recent studies have shown that subsequent characterisation of human MDSC subsets can be done with the expression of CD14 and CD15 molecules [25][26][27][28]. Identification of a CD11b + CD14 -CD15 + population with granulocyte morphology in renal cell carcinoma patients has been described as the human equivalent to GMDSCs in mice [29] (Table 1).…”

Treatment with lenalidomide induces immunoactivating and counter-regulatory immunosuppressive changes in myeloma patients

“…Reports on MDSC in human MM are scarce. To date, two publications report this cell type in MM patients, one describing an increased frequency of human leucocyte antigen D-related (HLA-DR) lo monocytes in patients with MM at various stages of their disease [14] and the other observing granulocytic MDSCs in the peripheral blood and bone marrow of MM patients [15]. A promising approach to counteract immunoinhibitory effects in MM is the implementation of immunotherapeutic agents such as lenalidomide (CC-5013, IMiD3, Revlimid), which is an effective drug in the treatment of newly diagnosed and relapsed MM.…”