|Year : 2018 | Volume
| Issue : 1 | Page : 2-8
Myeloid-derived suppressor cells and nonresolving inflammatory cells in glioma microenvironment: molecular mechanisms and therapeutic strategies
Xiao-Yan Ji1, Jia-Wei Ma2, Jun Dong1
1 Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
2 Department of Critical Care Medicine, Wuxi No.2 Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
|Date of Web Publication||28-Feb-2018|
Dr. Jia-Wei Ma
Department of Critical Care Medicine, Wuxi No.2 Hospital, Nanjing Medical University, Nanjing 214002, Jiangsu
Prof. Jun Dong
Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou 215004, Jiangsu
Source of Support: None, Conflict of Interest: None
Myeloid-derived suppressor cells (MDSCs) are a subgroup of immunosuppressive heterogeneous cells derived from bone marrow (BM) stem cells. They not only strongly inhibit T cell-mediated antitumor immune response but also directly induce tumorigenesis and promote tumor growth and metastasis. Besides, the nonresolving inflammation (NRI), a prime cause of tumor development, is present in the glioma microenvironment. However, the relationship between MDSCs and NRI, especially in the view of relevant molecular regulatory networks, has not been fully elucidated in gliomas. In the present study, the MDSC- and NRI-associated molecular regulatory network and key regulatory points are reviewed, and the targeted therapeutic strategies against gliomas are further discussed.
Keywords: Glioma, molecular regulatory network, myeloid-derived suppressor cells, nonresolving inflammation, target therapy, tumor microenvironment
|How to cite this article:|
Ji XY, Ma JW, Dong J. Myeloid-derived suppressor cells and nonresolving inflammatory cells in glioma microenvironment: molecular mechanisms and therapeutic strategies. Glioma 2018;1:2-8
|How to cite this URL:|
Ji XY, Ma JW, Dong J. Myeloid-derived suppressor cells and nonresolving inflammatory cells in glioma microenvironment: molecular mechanisms and therapeutic strategies. Glioma [serial online] 2018 [cited 2022 Jun 29];1:2-8. Available from: http://www.jglioma.com/text.asp?2018/1/1/2/226432
Xiao-Yan Ji and Jia-Wei Ma have contributed equally.
| Introduction|| |
In recent years, the myeloid-derived suppressor cells (MDSCs) and nonresolving inflammation (NRI) are regarded as the root causes of occurrence and development of cancers and are of high interest in oncology studies. However, the relationship between them remains unclear and is reviewed based on the current literature and our recent experimental studies.
| Myeloid-Derived Suppressor Cells and Nonresolving Inflammation in Glioma Microenvironment|| |
General characteristic of myeloid-derived suppressor cells
Under normal physiological conditions, immune inflammatory cells are derived from myeloid-derived hematopoietic stem cells and play an important role in the process of immune surveillance. These cells may transform into immunosuppressive cells when their host develop malignant tumor. MDSCs are obtained from terminally differentiated mature myeloid cells including macrophages, neutrophils, and dendritic cells (DCs). They may impair T cell activation by directly inducing regulatory T cells (Tregs) through production of transforming growth factor-β, while also suppressing the “killing effect” of natural killer (NK) cells and immune activity of mature DCs and T cells. The term “MDSCs” was coined by Gabrilovich et al. in 2007and were found to express a specific marker CD11b and Gr-1 protein. CD11b is a subunit of the β-2 integrin Mac-1, which is expressed in DCs, granulocytes, monocytes, and macrophages. The CD11b may regulate leukocyte adhesion and cell migration. The Gr-1 antigen is mainly expressed on the surface of macrophages/monocytes and granulocytes and is recognized by the RB6-8C5 antibody, which binds to the cell surface molecules Ly6G and Ly-6C. Pertaining to this, MDSCs are subdivided into Ly6G and Ly6C expressing subtypes in mice. The CD11b+Ly-6G low Ly-6C high cells have monocytic-like morphology and are named as monocytic-MDSCs, while the CD11b+Ly-6G high Ly-6C low cells have granulocyte-like morphology and are named as granulocyte-MDSCs. In addition to Gr-1 and CD11b, other markers have been used to characterize specific subsets of MDSCs. In tumor-bearing mice, CD11b+Gr-1+ cells may also express S100A9. Unlike mouse MDSCs, the human counterpart does not have a universal marker, and their phenotype is less well defined. In general, human MDSCs are defined as CD11b+CD33+ ALA-DR low/- cells, without expressing the markers of lymphoid or mature myeloid cells,, and they can promote tumor growth by nonimmune and immune mechanisms. The nonimmune mechanism functions through promoting tumor angiogenesis, while the immune mechanism takes several paths, as follows: (a) MDSCs-generated reactive oxygen species (ROS) and reactive nitrogen species (RNS) downregulate or block the synthesis of TcR CD33ζ chain, effecting the T cell activation; (b) MDSCs may also block T cell activation by depriving the environment of cysteine, an amino acid that is essential for T cell activation; (c) MDSCs may downregulate L-selectin (CD62L), a plasma membrane molecule that is necessary for the homing of naive T cells to lymph nodes, resulting in reduced CD4+ and CD8+ T cells activation as they are unable to migrate to lymph nodes where they would normally be activated by tumor.
In normal mice, the BM and spleen consist of about 20%–30% and 2%–4% of cells with MDSC phenotype, respectively, while none are found in the lymph nodes. Almost in all experimental models and patients, 75% of MDSC population is composed of G-MDSC and 25% of M-MDSC. However, on a per cell basis, the tumor suppressive character is more powerful in the M-MDSC than in the G-MDSC. In an analysis of MDSCs obtained from 28 glioma patients, the composition of MDSCs was 82% from CD33+CD15+
CD14-HLADR-(neutrophilic) cells, 3% from CD33+CD14+CD15-HLADR-(monocytic) cells, and 15% from CD33+CD15-CD14-HLADR-(lineage negative) cells. However, other studies reported the lineage-negative cells as the predominant ones. A similar pattern of MDSC composition is seen in renal cell carcinoma and bladder cancer, but with highest percentage of neutrophilic MDSCs in glioblastoma multiforme (GBM) population. In contrast, it is quite different in melanoma, where the percentage of three population of MDSCs is almost equal.
General characteristic of nonresolving inflammation
It is known that inflammation is a part of the complex biological response of organisms to harmful stimuli, such as pathogens, damaged cells, and irritants. Under normal circumstances, once the stimuli are eliminated, the inflammatory response is slowly reduced, which is generally termed as the resolving inflammation. The NRI is a long-term immoderate inflammation induced by constant low-intensity stimulation, and cannot be controlled by anti-inflammatory therapy, namely the inflammation exists either in progression or in latency forever.
Inflammation related to the occurrence and development of tumors was reported as early as 1960s. But back then, it was referred to the smoldering inflammation,, not the NRI. As to the relationship between NRI and cancer, Nathan and Ding  brought up the idea in 2010 that NRI was an uncontrollable inflammation and a common cause for many refractory diseases, including tumors. It is conceivable that the glioma-initiating cells are produced in the microenvironment of NRI, in which inflammation may induce the damage of DNA and subsequent instability of the genome and increase the incidence of gene mutation. The process may be repeated, which finally results in the dysfunction of DNA repairing and potential generation of tumor-initiating cells. Importantly, the NRI not only aggregates the gene mutations but also may activate some key signal pathways which control the survival, proliferation, angiogenesis, and invasion of glioma-initiating cells. In short, it is generally accepted that the genesis and development of tumors are related to the smoldering inflammation or NRI, but whether there is any functional difference between smoldering inflammation and NRI is still uncertain.
Effect of myeloid-derived suppressor cells on glioma
Fujita et al., have reported a substantial number of glioma-infiltrating CD11b+Gr-1+ cells in both de novo and transplantable syngeneic GL261 cell line mouse models, the depletion of which can inhibit the development of glioma. Furthermore, numerous circulating CD33+ HLADR-cells in peripheral blood of GBM patients have been detected, compared to healthy volunteers. In humans, healthy donor-derived CD14+ monocytes exposed to glioma cells may acquire MDSC-like properties, such as production of immunosuppressive cytokines-interleukin-10 (IL-10), TGF-β, and B7-H1, while also increasing the apoptosis of activated lymphocytes. As previously mentioned, some studies on GL261 murine glioma suggested that MDSC is a unique kind of monocyte/macrophage. However, others reported a strong association between degranulated neutrophils and T cell dysfunction in GBM patients, though with the immunosuppressive qualities of monocytic populations.
The MDSCs in the tumor foci need to be further amplified and activated in order to exert its inhibitory effect on tumor immune function. The amplification of MDSCs is induced by cytokines including cyclooxygenase-2 (COX-2), stem-cell factor (SCF), macrophage colony-stimulating factor (M-CSF), and vascular endothelial growth factor.,,, Signal transducer and activator of transcription-3 (STAT3) is the most important signal transcription factor to promote the proliferation of MDSCs. The MDSCs differentiated from hematopoietic progenitor cells, cocultured with tumor cells, or in tumor cell-conditioned medium can upregulate STAT3 expression, the inhibition of which may reduce the amplification/activation of the hematopoietic progenitor cell-derived MDSCs. STAT3 inhibitors or STAT3 knockout can also reduce the amplification of MDSC in tumor-bearing mice and can increase T cell activity. STAT3 activation can prevent the differentiation of myeloid progenitor cells and promote the amplification of MDSCs. STAT3 can regulate MDSCs amplification via the expression of S100A8 and S100A9. These receptors are expressed on the surface of MDSC's membrane and may promote the migration of MDSCs to tumor foci by binding to the carboxylated N-glycan receptors of cellular surface. In addition, MDSCs in the blood and secondary lymph nodes are reduced by carboxylated polysaccharide-specific antibody that blocks the binding of S100A8/S100A9 and MDSCs receptor. Delano et al. pointed out that to exert the inhibitory activity at their full potential, MDSCs need both amplification factors and activation factors. These activation factors (toll-like receptors, IL-13, IL-14, and TGF) are mainly produced by activated T cells and tumor stromal cells. Interferon gamma (IFN-γ), an immunity-promoting cytokine, can attenuate MDSC-mediated T cell suppression. STAT1 is the main transcription factor activated by IFN-γ signaling and involved in the regulation of inducible nitric oxide synthase (iNOS) and arginase activity. STAT1-deficient MDSCs are unable to inhibit T cell activation due to an inability to upregulate iNOS and arginase activity. In addition, IL-14 and IL-13 can also upregulate the arginase activity, thereby increasing the inhibitory activity of MDSCs.
The effects of continuously proliferating MDSCs in tumor tissue are as follows: (a) induction of angiogenesis and vasculogenesis. Tumor angiogenesis requires BM-derived endothelial progenitor cells (EPCs) recruitment, migration, and proliferation; certain growth factors or chemotherapeutic agents contributes to mobilization of EPCs from BM, which favors EPCs to be involved in tumor vasculogenesis; VEGFA, a major regulator on EPC proliferation and differentiation, can attract EPCs, the antibody against VEGFA can block the biological activities of VEGFA on EPCs;, both granulocyte colony-stimulating factor (G-CSF) and VEGFA can mobilize EPCs into peripheral circulation and promote angiogenesis; splenic MDSCs contribute to tumor vasculogenesis via directly differentiating into EPCs; (b) promotion of tumor invasion. MMP9 secreted by tumor and myeloid cells can promote tumor invasion. MicroRNA-494 and hypoxia-inducible factor 1α (HIF-1α) also have a role in regulating the non-immunological activity of MDSCs by up-regulation of MMP9 to enhancing the tissue infiltrating ability., Therefore, MDSCs, which secrete high levels of proteolytic enzymes, may contribute to tumor cell invasion into host stroma and blood. These contributions may result in increased circulating tumor cells and systemic metastasis.
Effect of RNI on glioma
In 2011, Korkaya et al. reported that the cancer stem cells (CSCs) might be regulated by the network of cytokines in inflammatory microenvironment and be a root of refractory tumors, including gliomas. The reason is that the interactions of inflammatory cytokines IL-1, IL-6, and IL-8, in turn, may activate STAT3/nuclear factor-kappa B (NF-κB) pathway in both tumor and stromal cells. Activation may further stimulate cytokine production, thus generating positive feedback loops. Research data show that the tumor-associated macrophages (TAMs) can influence cancer progression and metastasis by CLL18 production, which triggers integrin clustering that enhances cancer cell adherence to extracellular matrix. Furthermore, PITPNM3, a functional receptor for CCL18, may activate intracellular calcium signaling. Furthermore, CCL18 may promote metastasis and invasion of cancer xenografts, which may be abrogated after suppressing the PITPNM3. Glioma stem cells (GSCs), when transplanted into brain, abdomen, liver, and subcutaneous tissue, can induce malignant transformation of host macrophages and DCs, indicating that such malignant transformation may be a universal rule without limiting to tumor transplant site., Moreover, coculturing GSCs with BM cells in vitro can also induce malignant transformation of the latter. The gene expression profile of the above-related cells has been established using the microRNA chip method, and preliminary analysis shows that malignant transformation by GSCs may be achieved by microRNA-146a-5p-induced activation of the classical NF-κB pathway. It needs a special mention that the immortalized feature of BM-derived inflammatory cells, which underwent malignant transformation, is in accordance with the characteristics of NRI cells. The classically activated macrophage and alternatively activated macrophage (TAMs) are termed as M1 and M2, respectively. Although both have obvious differences in molecular expression, further study is necessary to elucidate the differences in chromosome and other cytogenetic levels.
Molecular Regulation of Nonresolving Inflammation and Myeloid-Derived Suppressor Cells in Tumor (Glioma) Microenvironment
In the tumor microenvironment, despite their obvious difference in the “time of entry” into the tumor tissues, both NRI cells and MDSCs possess similar effect on tumors, including tumor growth, revascularization, and metastasis. It remains unclear how they interact with each other at the molecular level. This section only summarizes the current research achievement in this regard. At the stage of tumor initiation, NRI cells may release large amount of ROS and RON that induce DNA damage and mutations. These free radicals can also downregulate or silence the mismatch repair protein, by removing proto-oncogenes MSH2/MSH6 promoter, which results in generation and accumulation of whole-genome DNA replication errors. In addition, ROS can also inactivate tumor suppressor gene p53 and activate proto-oncogene Ras within cancer cells and inflammatory epithelial cells. The upregulation of NO-induced DNA methyltransferase can result in the large amount of cytosine methylation and inactivation of tumor suppressor genes P16INK4α and E-cadherin. Further, cytidine deaminase can also induce a variety of gene mutations including p53, c-Myc, and Bcl-6. Therefore, impaired DNA repair will result in tumor-initiating cells. The persistence of inflammatory injury will further enhance the cloning capabilities of the tumor-initiating cells, thus increasing the genomic instability and cellular heterogeneity, which finally leads to formation of tumors. Further development of the tumors needs activation of NF-kB and STAT3 pathways, through the signal stimulation produced by neighboring cells.
The MDSCs, a subgroup of neighboring cells in tumor microenvironment, together with tumor cell itself, can promote tumor growth and metastasis through autocrine or paracrine secretion of inflammatory cytokines, growth factors, and chemokines, etc. Among them, STAT3 plays a key role in the regulation of biological behaviors of the tumors and immune cells., On the other hand, MDSCs can also promote the differentiation of Tregs by releasing TGF-β and inhibit the “killing effect” of NK cells and the immune activities of mature DCs and T cells. Many studies have shown that STAT3 activation is critically important for the suppressive activity of MDSCs, the inhibition of which may also abolish the effect.,,,, Some inflammatory cytokines, for example IL-6, can activate the STAT3 and subsequently affect the generation, migration, and activity of MDSCs via signal transducer and STAT3 activator. In addition, NF-κB is a transcription factor that controls the expression of various genes involved in the immune response. Under normal physiological conditions, NF-κB is present in the cytoplasm, in an inhibited status via binding to IκB. The phosphorylation of IκB by inflammatory cytokines may result in the NF-κB activation, which may activate its downstream target genes including tumor cell proliferation genes (cyclins and c-Myc), angiogenic genes (VEGP and CXCL12), and antiapoptotic genes (c-IAP, Bcl-Xl, Bcl-2, and c-FLIP). As for the relationship between STAT3 and NF-κB, there have been reports that the maintenance of NF-κB activity in tumors requires STAT3, which is also frequently constitutively activated in cancer, such as glioma. Most inflammatory signals may affect tumorigenesis by activating STAT3 and NF-κB. Persistent STAT3 activation in malignant cells may stimulate the tumor survival, invasion, angiogenesis, proliferation, and tumor-induced inflammation. In addition, STAT3 activation within immune cells may induce the differentiation and recruitment of immature myeloid cells. Furthermore, other studies have indicated that IL-6-janus kinase (JAK)-STAT3 axis is the main form of STAT3 activation. IL-6 is the downstream product of NF-κB, and it is mainly obtained from the stromal cells in the microenvironment. Binding of IL-6 onto the IL-6 receptor is followed by activation of the JAKs, which in turn phosphorylates and activates the transcription factor STAT-3. Moreover, growth factors and nonreceptor tyrosine kinases, such as SRC and ABL, can also activate the STAT3 pathway, which results in the inflammation-associated gene expression, massive new angiogenesis, and tumor cell proliferation. In conclusion, activation of STAT3 may be necessary for the maintenance of positive feedback loop between tumor cells and immune cells to induce the inflammation and tumor growth.
| Therapeutic Targets of Myeloid-Derived Suppressor Cells and Nonresolving Inflammation|| |
Therapeutic targets of myeloid-derived suppressor cells
MDSCs play an important role in regulation of tumor growth, which has aroused intense interest in the development of novel therapeutic strategies against these cells. The potential strategies can be placed into four categories: (a) promoting the differentiation and maturation of MDSCs – all-trans retinoic acid (ATRA) may promote the differentiation of MDSCs into DCs and improve their immune-stimulatory ability. Treatment of renal cell carcinoma patients with ATRA has shown to obviously decrease the percentage of MDSCs in peripheral blood. Pan et al. reported that SCF can promote the differentiation and development of MDSCs. SiRNA-mediated suppression of SCF gene can significantly reduce MDSCs amplification and restore immune activity of T cells. (b) Suppressing the amplification of MDSCs – a variety of cytokines produced by tumor cells can induce amplification and recruitment of MDSCs, which can be inhibited by blocking the function of cytokines. Avastin, a VEGF-specific blocking antibody, can effectively reduce the number of MDSCs in peripheral blood of patients with metastatic renal cell carcinoma. (c) Blocking the function of MDSCs – the ROS, iNOS, and ARG-1 play a vital role in the process of MDSC-mediated immune suppression. Inhibiting or blocking the signal or function of these molecules is a good strategy for immunotherapy. For example, COX2 inhibitor can inhibit the prostaglandin F2 secretion by tumor cells, which further inhibits the activity of MDSC Arg-1 to reenergize T cells' tumor responses. (d) Reducing the number of MDSCs – the MDSCs can be decreased by low doses of chemotherapy. In mouse models, gemcitabine, an anticancer drug in clinical application, has been shown to deplete the MDSCs without deleterious effects on T cells, which contributes to the reduction of tumor growth and prolongation of survival time.
Therapeutic targets of nonresolving inflammation
It is mainly focused on the negative interference of inflammatory cells and factors in tumor microenvironment, especially in the cytokine-mediated signaling pathways. A more optimistic target for both MDSCs and NRI is STAT3, a common signaling pathway, suggesting that STAT3 inactivation may exert a powerful anti-inflammatory effect. Some specific inhibitors can block the upstream signals of STATs or directly affect the target STAT protein. Several small-molecule inhibitors have been developed, which can inhibit the STAT3-dependent cell malignant transformation and tumor cell proliferation and also induce the apoptosis of tumor cells via the inhibition of STAT3 signaling pathway. These inhibitors have no obvious adverse effects on normal cell growth. In addition, inhibition of multiple gene expressions may be more effective in suppressing tumor growth, which can be achieved through RNA interference technology. Targeted therapy against STAT3 with siRNA has been successfully applied to inhibit various cancer cell lines, including glioma cells.
| Conclusion|| |
Tumor microenvironment consists of mature immune cells including macrophages, neutrophils, mast cells, DCs, NK cells, resident cells such as fibroblasts and endothelial cells, and adaptive immune cells, such as T and B lymphocytes. MDSCs and NRI cells also participate in the process and may exert a special role at different stages of tumor progression. It is an indisputable fact that the tumor-initiating cells start at the resolving inflammatory phase, gain unlimited growth ability and self-renewal ability in the NRI phase, and finally change to CSCs which can proliferate indefinitely. The MDSCs refer to those myeloid-derived immune inflammatory cells which are accumulated in tumor-progressive stage. They are found in tumors or in the spleen, lymph node, and circulating blood even before invasion. As known, both MDSCs and NRI cells can stimulate the tumor growth as the inflammatory cells in tumor microenvironment and thus are categorized as tumor-related cells [Figure 1].
|Figure 1: The schematic diagram of related molecular regulation of nonresolving inflammation, myeloid-derived suppressor cells, and glioma. Glioma cells release the pro-inflammatory cytokines and chemokines that promote the uncontrolled proliferation of inflammatory cells, leading to loss of immune function in myeloid-derived cells. The two types of cells may secrete interleukin-6 to promote tumor growth. The intracellular signal transducer and activator of transcription-3 and NF-κB can be activated by interleukin-6 and tumor necrosis factor alpha, and their activation can not only promote the growth of tumors but also promote the proliferation and activation of myeloid-derived suppressor cells. Interleukin-6 links signal transducer and activator of transcription-3 and NF-κB signal pathways; thus, the interaction between signal transducer and activator of transcription-3 NF-κB is the key control hub|
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The MDSCs represent a heterogenic population of immature myeloid cells that consist of myeloid progenitors and precursors of macrophages, DCs, and granulocytes, while the resolving inflammatory cells are a group of mature granulocytes and lymphocytes. It has not been verified that whether the NRI cells are the same as resolving inflammatory cells for mature cells. In fact, MDSCs are irrepressible with clinical interference, but whether they have the immortalization capability as CSCs is worth further studies. However, it should be a good practice to simultaneously treat both NRI cells and MDSCs in tumor microenvironment, along with cancer cells, in clinical practice. This treatment may prove beneficial toward tumor resolution through alteration of tumor microenvironment.
Financial support and sponsorship
This work was supported by the National Natural Science Foundation of China grant 81572489 (Q. C), 81502175 (B.L).
Conflicts of interest
There are no conflicts of interest.
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