Mesenchymal Stromal Cells: Regulators of Immune Response in Hematological Malignancies

Review Article

J Blood Disord. 2015;2(1): 1022.

Mesenchymal Stromal Cells: Regulators of Immune Response in Hematological Malignancies

Poggi A¹* and Zocchi MR²

1Molecular Oncology and Angiogenesis Unit, National Institute for Cancer Research, Italy

2Division of Immunology, Transplants and Infectious Diseases, Scientific Institute San Raffaele Milan, Italy

*Corresponding author: Poggi A, Molecular Oncology and Angiogenesis Unit, Largo R. Benzi 10, CBA-ISTNord Tower A1 and C4, IRCCS AOU San Martino IST National Institute for Cancer Research-Genoa, 16132-Genoa, Italy.

Received: December 02, 2014; Accepted: February 11, 2015; Published: February 27, 2015


The Bone Marrow (BM) microenvironment plays a key role in regulating the maturation of precursors of myeloid and B lymphoid cells. This microenvironment is composed of several types of cells among which Mesenchymal Stromal Cells (MSC) can be considered as a major component. Indeed, these elements produce several extracellular matrix proteins involved in triggering signals to precursors cells; furthermore, MSC posses the high plasticity to differentiate into other cell components present within BM as osteocytes and adipocytes which regulate the composition of the microenvironment. MSC can display an immunoregulatory activity leading to the impairment of recognition of leukemic transformed cells. There are preclinical and clinical evidences that treatment with Immunomodulatory Drugs (IMiDs) in multiple myeloma and aminobisphosphonates in different hematological malignancies can trigger an efficient immune response; this response can hit both tumor and stromal cell component of the BM. Herein, we briefly summarize the more recent advances on how and what MSC can regulate anti-leukemic immune response and which drugs would be employed to render MSC immunostimulatory rather than immunosuppressive.

Keywords: MSC; NK; γδT cells; NKG2D; NKG2DL; Immunosuppression


APC: Antigen Presenting Cells; BM: Bone Marrow; CLL: Chronic Lymphocytic Leukemia; COX2: Cyclooxigenase 2; CTLs: Cytolytic T Lymphocytes; DC: Dendritic Cells; EGF: Epidermal Growth Factor; EGFR: Epidermal Growth Factor Receptor; EMC: Extracellular Matrix Component; EMT: Epithelial Mesenchymal Transition; HLA: Human class I Leukocyte Antigen; HL: Hodgkin Lymphoma; HSC: Hemopoietic Stem Cells; IDO: Indoleamine 2,3, Deoxigenase; IL-: Inteleukin-; IFNγ: Interferon γ; IMiDs: Immunomodulatory Drugs; LCA: Leukocyte Common Antigen; LNMSC: Lymph Node MSC; LSC: Leukemic Stem Cells; MDSC: Myeloid-Derived Suppressor Cells; MHC: Major Histocompatibility Complex; MICA/B: MHC Class I polypeptide related sequence A/B; MM: Multiple Myeloma; MSC: Mesenchymal Stromal Cells; N-BP: aminobisphosphonates; NK cell: Natural Killer cell; NHL: Non-Hodgkin Lymphoma; NKG2D: Natural-Killer Group 2 member D; NKG2DL: NKG2D Ligand; NKT: Natural Killer-like T cells; NOS2: Nitric Oxidase Synthase 2; PB: Peripheral Blood; PGE2: Prostaglandin E2; P4H: Prolyl-4- Hydroxilase; SCF: Stem Cell Factor; SDF1: Stromal Derived Factor 1; Th: T helper; TNFa: Tumor Necrosis Factor a; TGFβ: Transforming Growth Factor β; TPO: Trombopoietin; Treg; regulatory T cells; ULBP1-6: UL16 Binding Protein 1-6; VEGF: Vascular Endothelial Growth Factor


Within the BM, leukemic cells interact with the microenvironment composed of different kind of cells, soluble factors and Extracellular Matrix Components (EMC) [1,2]. Mesenchymal Stromal Cells (MSC) can influence their surroundings producing EMC and soluble factors playing a role in maturation of hematopoietic cell precursors. Furthermore, MSC can regulate both innate and adaptive immune cell response [3]. It is becoming evident that MSC plays a key role in the development of the leukemic disease [1,2]. Herein, we will point out on the use of drugs to regulate MSC-mediated activities and we will analyze more recent findings regarding the immunosuppressive role of MSC. Indeed, we believe that influencing MSC behavior one can also affect the development and the fate of the leukemic diseases.

Complexity of bone marrow microenvironment: relevance of MSC

Generally, the leukemic microenvironment in BM is composed of cancer cells at different stages of maturation, endothelial cells, immune cells, myeloid cells, EMC and different types of MSC [1-6]. These MSC can be fibroblasts which produce and secrete the collagen component of the extracellular matrix, osteocytes and adipocytes which are involved in the mineralization of the EMC or in the storing of fatty acids respectively. Further due to the anatomic site, also the interaction with endothelial cells or pericytes located at the vascular sinusoid component of BM can influence the destiny of leukemic cells during their egression from BM to Peripheral Blood (PB) [5,6]. Indeed, the endothelium senses the microenvironment modifications controlling the trafficking of leukemic cells and different stem cell precursors [7]; further, endothelial cells can influence the fate of Hematopoietic Stem Cell (HSC) precursors releasing VEGF and angiopoietin 1 and 2. It is to note that within the BM the amount of a component of the microenvironment is not the same at the different sites; this leads to a different influence on the growth of leukemic cell [6-8]. There are some evidences in the literature that subsets of MSC can differentiate to endothelial cells suggesting that also this BM microenvironment component derives from MSC. In addition, inside the BM, several types of monocyte-derived cells are present [5]. Macrophages, dendritic cells in different stages of differentiation, histiocytes, fibrocytes, Myeloid Derived Suppressors Cells (MDSC) can function as scavengers, professional Antigen Presenting Cells (APC), extracellular matrix producer or immunoregulatory elements together with the other components of BM [5]. Also, these cells are really difficult to be distinguished from MSC on the basis of their morphology, expression of defined molecular markers and functions [9]. In this complex scenario, MSC can regulate the proliferation and maturation of HSC precursors [7] through the Jagged 1, Delta 1, Trombopoietin (TPO) and Stem Cell Factor (SCF) and for these reasons MSC may be considered as one of the first cell which may sense the neoplastic transformation [8]. Indeed, it has been claimed that Leukemic Stem Cells (LSC) are responsible for the onset of leukemia; however, the functional MSC behavior is essential to favor or impede the LSC expansion [6-8]; for this reason MSC should be considered as a target to treat leukemia’s [9-11]. In addition, BM is a store of totipotent undifferentiated MSC, thus tumor cell precursors may affect the differentiation of MSC in the tumor niche and determine the fate of leukemia suggesting a strong relevance for the cross-talk between MSC and LSC [6-8]. It is of note that MSC can produce Transforming Growth Factor (TGF) β which is known to play a key role within the BM niche [12]; indeed, it has been shown that TGFβ can inhibit the cytokine-triggered clustering of lipid rafts and it induces HSC hibernation ex vivo. The surface downstream mediators of TGFβ signaling as Smad2 and Smad3 are specifically activated in HSCs in the hibernation state, but not in proliferating CD34+ progenitor’s cells [12]. These data would indicate that TGFβ is a candidate to control of HSC hibernation suggesting that this cytokine can model the HSC niche [12]. Further, MSC can produce IL6 that is a key cytokine for the growth and maturation of B lymphocytes and Multiple Myeloma (MM) cells [5] indicating that MSC within BM are essential for both normal and neoplastic development [5-10]. We should further note that in several reports the definition of stromal cells is not limited to MSC but also to monocyte-derived elements and endothelial cells. This leads to a confounding ground which does not aid to define precisely and unequivocally the BM scenario [1-4].

Phenotype and immunoregulatory role of BM-derived MSC

MSC isolated from the BM and expanded in vitro cell culture express CD73 CD105 CD146 and CD90 but not hematopoietic lineage markers as CD34 or the Leukocyte Common Antigen (LCA). They can produce different kinds of collagens and express the prolyl-4- hydroxylase which is the enzyme involved in the hydroxylation of prolyn residues of collagen. The MSC can be distinguished from monocytes as they do not express the CD14 marker and from professional APC by the lack of expression of B7-1 (CD80) and B7-2 (CD86) surface molecules [13]. However, MSC can share several markers and functions with other microenvironment components and this can depend on either the experimental conditions used for their in vitro culture expansion or it is related to the tissue specimen from which they are isolated [9,13,14]. For these reasons, some challenging questions have been raised regarding the use of MSC as a tool for modulating immune response [14]. Indeed, it has been proposed that MSC should be subjected to a process termed ‘licensing’ to get the ability to regulate immune response. The licensing process would consist of different steps as activation with pro-inflammatory cytokines such as IFNγ. TNFa and IL1a or IL1β, b) the prevalence of stimuli as Toll ligands which favor rather than hamper the inhibiting behavior of MSC and finally c) the moment at which MSC are involved together the activation signal delivered to immune effectors cells. It appears that the direct interaction between MSC and lymphocyte is a relevant requisite for the delivery of the inhibiting signal [13]. This inhibiting effect, although mainly contact dependent, is mediated through different soluble factors as IL10, TGFβ, IFNγ, TNFa, IL1β, hepatocyte growth factor, heme oxygenase, indoleamine 2-3 dioxygenase, prostaglandin E2, nitric oxide and peculiar histocompatibility antigens as HLAG5 [13-15] (Figure 1). These factors, with several and still undefined mediators, can apparently function alone or in association depending on the origin and ontogenic stage of MSC. This picture is somehow too complex to be checked to use MSC in clinical setting and it would suggest that the “primum movens” of the commitment of an inhibiting MSC is not defined yet. Whatever the molecular mechanism underlined, MSC can deliver in vitro a negative signal on several subset of T and non-T lymphocytes blocking proliferation to either antigenic, polyclonal or oligoclonal stimuli such as phytohemoagglutinin A or monoclonal antibodies to CD3/ T cell receptor complex [13-16]. This inhibiting effect is evident when the ratio between T lymphocyte and MSC are similar and it progressively decreased when the amount of responding lymphocytes increase. This finding indicates that MSC cannot modulate immune response in the presence of an excess of lymphocytes, suggesting that an increment of anti-tumor effectors cells could overcome inhibitory signals mediated within the BM microenvironment. Conflicting reports have been reported regarding the effects on B lymphocytes both in vitro and in vivo experimental settings [17-19]. Indeed, it has been shown that Immunoglobulin (Ig) synthesis is either inhibited [17] or triggered if B cells are stimulated either through the engagement of B cell receptor or via Toll like Receptors (TLR) respectively [18]. Conflicting results have been also reported on the possibility that MSC may trigger rather than inhibit the generation of cytotoxic T lymphocytes and that MSC can function as stimulator in mixed lymphocyte reaction [15,20]. On the other hand, it has been claimed that also the generation of Treg cells is another relevant mechanisms by which MSC can regulate immune response [21-23]. Also in this case not all reports indicate a relevant role for these cells [24].

Citation: Poggi A and Zocchi MR. Mesenchymal Stromal Cells: Regulators of Immune Response in Hematological Malignancies. J Blood Disord. 2015;2(1): 1022.