myeloid-derived suppressor cell

MDSCs are formed from bone marrow precursors when myelopoietic processes are interrupted, caused by several illnesses.{{Citation| vauthors = Fan D, Raychoudhury S, Ai W |title=KLF4-Mediated Plasticity of Myeloid-Derived Suppressor Cells (MDSCs)|date=2020-05-13|work=Cells of the Immune System|publisher=IntechOpen|doi=10.5772/intechopen.89151 |isbn=978-1-78985-583-8 |s2cid=209582254 |doi-access=free}}{{cite journal | vauthors = Ouzounova M, Lee E, Piranlioglu R, El Andaloussi A, Kolhe R, Demirci MF, Marasco D, Asm I, Chadli A, Hassan KA, Thangaraju M, Zhou G, Arbab AS, Cowell JK, Korkaya H | display-authors = 6 | title = Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade | journal = Nature Communications | volume = 8 | issue = 1 | pages = 14979 | date = April 2017 | pmid = 28382931 | doi = 10.1038/ncomms14979 | pmc = 5384228 | bibcode = 2017NatCo...814979O }} Cancer patients' growing tumors produce cytokines and other substances that affect MDSC development. Tumor cell lines overexpress colony-stimulating factors (G-CSF and GM-CSF) and [https://www.ncbi.nlm.nih.gov/gene/3569 IL6], which promote development of MDSCs that have immune suppressive function in vivo. Other cytokines, including [https://www.ncbi.nlm.nih.gov/gene/3586 IL10], [https://www.ncbi.nlm.nih.gov/gene/111343 IL1], VEGF, and PGE2 have been associated with the formation and regulation of MDSCs. GM-CSF promotes synthesis of MDSCs from bone marrow, and the transcription factor c/EBP regulates development of MDSCs in bone marrow and in tumors. STAT3 also promotes development of MDSCs, whereas IRF8 could counteract MDSC-inducing signals.{{cite journal | vauthors = Poschke I, Kiessling R | title = On the armament and appearances of human myeloid-derived suppressor cells | journal = Clinical Immunology | volume = 144 | issue = 3 | pages = 250–268 | date = September 2012 | pmid = 22858650 | doi = 10.1016/j.clim.2012.06.003 }}

MDSCs migrate as immature cells from the bone marrow to peripheral tissues (or tumors), where they differentiate into mature macrophages, dendritic cells, and neutrophils without suppressive phenotypes under homeostatic conditions, but become polarized when exposed to pro-inflammatory compounds, chemokines, and cytokines. In the tumor microenvironment, they suppress the anti-tumor immune response. The presence of MDSCs has been associated with progression of colon cancer, tumor angiogenesis, and metastases. In addition to producing NO and ROS, MDSCs secrete immune-regulatory cytokines such as TNF, [https://www.ncbi.nlm.nih.gov/gene/7040 TGFB], and [https://www.ncbi.nlm.nih.gov/gene/3586 IL10]. There are subpopulations of MDSC that have some common suppressive characteristics but also have their own unique features; different subpopulations can be found in different areas of the same tissue or tumor.{{Cite journal| vauthors = Gabrilovich D |title=Abstract IA7: Regulation of myeloid-derived suppressor cells in tumor micro-environment |journal=Cancer Research |date=2013-01-01 |volume=73 |pages=IA7 |publisher=American Association for Cancer Research|doi=10.1158/1538-7445.tumimm2012-ia7}} Tumor-infiltrating MDSCs develop in response to environmental factors, upregulating CD38 (which removes NAD from the environment and is necessary for mitochondrial biosynthesis), PDL-1 (an immune checkpoint protein) and LOX1 (promotes fatty acid consumption and fatty acid oxidation). Tumor-infiltrating MDSCs also secrete exosomes that can inhibit the anti-tumor immune response.

Myeloid-derived suppressor cells (MDSCs) are a recently discovered bone-marrow-derived cell type. They have characteristic of immature stem cells with immunomodulatory properties. In fact, they are used in research to develop therapeutic strategies against both autoimmune diseases and exacerbate inflammation, which has special interest in the central nervous system. The main inconvenient of MDSCs is that they are only formed during inflammatory conditions, thus being commonly gathered from diseased subjects.{{Cite journal |last1=Melero-Jerez |first1=Carolina |last2=Alonso-Gómez |first2=Aitana |last3=Moñivas |first3=Esther |last4=Lebrón-Galán |first4=Rafael |last5=Machín-Díaz |first5=Isabel |last6=de Castro |first6=Fernando |last7=Clemente |first7=Diego |date=July 2020 |title=The proportion of myeloid-derived suppressor cells in the spleen is related to the severity of the clinical course and tissue damage extent in a murine model of multiple sclerosis |url=https://linkinghub.elsevier.com/retrieve/pii/S0969996120301443 |journal=Neurobiology of Disease |language=en |volume=140 |pages=104869 |doi=10.1016/j.nbd.2020.104869|pmid=32278882 |hdl=10261/219706 |hdl-access=free }}{{Cite journal |last1=Melero-Jerez |first1=Carolina |last2=Fernández-Gómez |first2=Beatriz |last3=Lebrón-Galán |first3=Rafael |last4=Ortega |first4=Maria Cristina |last5=Sánchez-de Lara |first5=Irene |last6=Ojalvo |first6=Ana Cristina |last7=Clemente |first7=Diego |last8=de Castro |first8=Fernando |date=April 2021 |title=Myeloid-derived suppressor cells support remyelination in a murine model of multiple sclerosis by promoting oligodendrocyte precursor cell survival, proliferation, and differentiation |journal=Glia |language=en |volume=69 |issue=4 |pages=905–924 |doi=10.1002/glia.23936 |issn=0894-1491 |pmc=7894183 |pmid=33217041}}{{Cite journal |last1=Melero-Jerez |first1=Carolina |last2=Ortega |first2=María Cristina |last3=Moliné-Velázquez |first3=Verónica |last4=Clemente |first4=Diego |date=March 2016 |title=Myeloid derived suppressor cells in inflammatory conditions of the central nervous system |url=https://linkinghub.elsevier.com/retrieve/pii/S0925443915003154 |journal=Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease |language=en |volume=1862 |issue=3 |pages=368–380 |doi=10.1016/j.bbadis.2015.10.015|pmid=26527182 }}

However, a recent research of the University of Salamanca has demonstrated that immature myeloid cells (IMCs), the precursors of MDSCs, have also potential immunosuppressive activity under pathological conditions.{{Cite journal |last1=del Pilar |first1=Carlos |last2=Garrido-Matilla |first2=Lucía |last3=del Pozo-Filíu |first3=Lucía |last4=Lebrón-Galán |first4=Rafael |last5=Arias |first5=Raúl F. |last6=Clemente |first6=Diego |last7=Alonso |first7=José Ramón |last8=Weruaga |first8=Eduardo |last9=Díaz |first9=David |date=2024-02-14 |title=Intracerebellar injection of monocytic immature myeloid cells prevents the adverse effects caused by stereotactic surgery in a model of cerebellar neurodegeneration |journal=Journal of Neuroinflammation |language=en |volume=21 |issue=1 |page=49 |doi=10.1186/s12974-023-03000-8 |doi-access=free |issn=1742-2094 |pmc=10867997 |pmid=38355633}} IMCs can be directly gathered from healthy bone marrow, which is a more clinically feasible source. Then, IMCs under pathological conditions behave as MDSCs exerting immunomodulation. In this sense, IMCs can be directly used thus avoiding their gathering from diseased subjects.{{Cite journal |last1=del Pilar |first1=Carlos |last2=Garrido-Matilla |first2=Lucía |last3=del Pozo-Filíu |first3=Lucía |last4=Lebrón-Galán |first4=Rafael |last5=Arias |first5=Raúl F. |last6=Clemente |first6=Diego |last7=Alonso |first7=José Ramón |last8=Weruaga |first8=Eduardo |last9=Díaz |first9=David |date=2024-02-14 |title=Intracerebellar injection of monocytic immature myeloid cells prevents the adverse effects caused by stereotactic surgery in a model of cerebellar neurodegeneration |journal=Journal of Neuroinflammation |language=en |volume=21 |issue=1 |page=49 |doi=10.1186/s12974-023-03000-8 |doi-access=free |issn=1742-2094 |pmc=10867997 |pmid=38355633}}

In addition, IMCs are promising adjuvants when performing neurosurgery. They application in an intracranial surgery almost completely prevented the impairments caused by this procedure in mice, probably by the modulation of the inflammatory patterns.{{Cite journal |last1=del Pilar |first1=Carlos |last2=Garrido-Matilla |first2=Lucía |last3=del Pozo-Filíu |first3=Lucía |last4=Lebrón-Galán |first4=Rafael |last5=Arias |first5=Raúl F. |last6=Clemente |first6=Diego |last7=Alonso |first7=José Ramón |last8=Weruaga |first8=Eduardo |last9=Díaz |first9=David |date=2024-02-14 |title=Intracerebellar injection of monocytic immature myeloid cells prevents the adverse effects caused by stereotactic surgery in a model of cerebellar neurodegeneration |journal=Journal of Neuroinflammation |language=en |volume=21 |issue=1 |page=49 |doi=10.1186/s12974-023-03000-8 |doi-access=free |issn=1742-2094 |pmc=10867997 |pmid=38355633}} In this sense, IMCs have a direct pre-clinical application to minimize the secondary effects inherent to every single intracranial surgery, especially in a diseased environment.

MDSCs derive from bone marrow precursors usually as the result of a perturbed myeloipoiesis caused by different pathologies. In cancer patients, growing tumors secrete a variety of cytokines and other molecules which are key signals involved in the generation of MDSC. Tumor cell lines overexpressing colony stimulating factors (e.g. G-CSF and GM-CSF) have long been used in vivo models of MDSC generation. GM-CSF, G-CSF and IL-6 allow the in vitro generation of MDSC that retain their suppressive function in vivo. In addition to CSF, other cytokines such as IL-6, IL-10, VEGF, PGE2 and IL-1 have been implicated in the development and regulation of MDSC.{{cite journal | vauthors = Gros A, Turcotte S, Wunderlich JR, Ahmadzadeh M, Dudley ME, Rosenberg SA | title = Myeloid cells obtained from the blood but not from the tumor can suppress T-cell proliferation in patients with melanoma | journal = Clinical Cancer Research | volume = 18 | issue = 19 | pages = 5212–23 | date = October 2012 | pmid = 22837179 | pmc = 6374773 | doi = 10.1158/1078-0432.CCR-12-1108 }} The myeloid-differentiation cytokine GM-CSF is a key factor in MDSC production from bone marrow,{{cite journal | vauthors = Liechtenstein T, Perez-Janices N, Gato M, Caliendo F, Kochan G, Blanco-Luquin I, Van der Jeught K, Arce F, Guerrero-Setas D, Fernandez-Irigoyen J, Santamaria E, Breckpot K, Escors D | display-authors = 6 | title = A highly efficient tumor-infiltrating MDSC differentiation system for discovery of anti-neoplastic targets, which circumvents the need for tumor establishment in mice | journal = Oncotarget | volume = 5 | issue = 17 | pages = 7843–57 | date = September 2014 | pmid = 25151659 | pmc = 4202165 | doi = 10.18632/oncotarget.2279 }}{{Unreliable medical source|date=April 2021}} and it has been shown that the c/EBPβ transcription factor plays a key role in the generation of in vitro bone marrow-derived and in vivo tumor-induced MDSC. Moreover, STAT3 promotes MDSC differentiation and expansion and IRF8 has been suggested to counterbalance MDSC-inducing signals.

Murine MDSCs show two distinct phenotypes which discriminate them into either monocytic MDSCs or granulocytic MDSCs. The relationship between these two subtypes remains controversial, as they closely resemble monocytes and neutrophils respectively. While monocyte and neutrophil differentiation pathways within the bone marrow are antagonistic and dependent on the relative expression of IRF8 and c/EBP transcription factors (and hence there is not a direct precursor-progeny link between these two myeloid cell types), this seems not to be the case for MDSCs. Monocytic MDSCs seem to be precursors of granulocytic subsets demonstrated both in vitro and in vivo.{{cite journal | vauthors = Youn JI, Kumar V, Collazo M, Nefedova Y, Condamine T, Cheng P, Villagra A, Antonia S, McCaffrey JC, Fishman M, Sarnaik A, Horna P, Sotomayor E, Gabrilovich DI | display-authors = 6 | title = Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer | journal = Nature Immunology | volume = 14 | issue = 3 | pages = 211–20 | date = March 2013 | pmid = 23354483 | pmc = 3578019 | doi = 10.1038/ni.2526 }} This differentiation process is accelerated upon tumor infiltration and possibly driven by the hypoxic tumor microenvironment.

The depletion of MDSCs from mice with liver cancer significantly increases natural killer (NK) cell cytotoxicity, NKG2D expression, and IFNg (IFNg) production and induces NK cell energy.{{cite journal | vauthors = Zhao Y, Wu T, Shao S, Shi B, Zhao Y | title = Phenotype, development, and biological function of myeloid-derived suppressor cells | journal = Oncoimmunology | volume = 5 | issue = 2 | pages = e1004983 | date = February 2016 | pmid = 27057424 | doi = 10.1080/2162402x.2015.1004983 | pmc = 4801459 }} MDSC depletion restored the function of impaired hepatic NK cells. An MDSC derived from chronic inflammation caused T and NK-cell dysfunction along with downregulation of the TCR z chain (CD247). The immunosuppressive milieu directly affects CD247, which is crucial in initiating immune responses. MDSCs, acting through membrane-bound TGF-b1, inhibit NK cells in tumor-bearing hosts due to the activity of TGF-b1 on MDSCs. Therefore, MDSCs constitutively suppress hepatic NK cells in tumor-bearing hosts through TGF-b1 on MDSCs.{{Cite journal| vauthors = Engwerda C |date=2013-04-26|title=Faculty Opinions recommendation of Tumor necrosis factor-α blocks differentiation and enhances the suppressive activity of immature myeloid cells during chronic inflammation.|doi=10.3410/f.718002932.793475483 |doi-access=free}}

A number of studies have reported MDSC regulation of B-cell responses to activators and mitogens that are not MHC-regulated, as well as antigen-specific T cell responses. An infection with the LP-BM5 retrovirus can cause acquired immune deficiency in mice, which causes highly immunosuppressive CD11bCGr-1CLy6CC MDSCs. These cells suppress T and B cells by signaling via nitric oxide (NO).{{cite journal | vauthors = Green KA, Cook WJ, Green WR | title = Myeloid-derived suppressor cells in murine retrovirus-induced AIDS inhibit T- and B-cell responses in vitro that are used to define the immunodeficiency | journal = Journal of Virology | volume = 87 | issue = 4 | pages = 2058–2071 | date = February 2013 | pmid = 23221564 | pmc = 3571497 | doi = 10.1128/jvi.01547-12 }}

Immune responses against tumors and infections are regulated by myeloid-derived suppressor cells and dendritic cells (DCs). The combination of LPS and IFNg treatment of bone marrow-derived MDSCs limits DC formation and improves MDSC suppressive action. MDSCs have been shown to reduce the effectiveness of DC vaccinations. MDSC frequency has no effect on DC production or survivability, but it does cause a dose-dependent reduction in DC maturation. High CD14CHLA-DR/low cell frequencies can stifle DC maturation and decrease DC function, both of which are critical for vaccination effectiveness. As a result, the balance between MDSCs and DCs might be crucial in tumor and infection treatment. Thus, the balance between MDSCs and DCs may play an important role in tumor and infection therapy.{{cite journal | vauthors = Greifenberg V, Ribechini E, Rössner S, Lutz MB | title = Myeloid-derived suppressor cell activation by combined LPS and IFN-gamma treatment impairs DC development | journal = European Journal of Immunology | volume = 39 | issue = 10 | pages = 2865–2876 | date = October 2009 | pmid = 19637228 | doi = 10.1002/eji.200939486 | s2cid = 26342683 | doi-access = free }}{{cite journal | vauthors = Poschke I, Mao Y, Adamson L, Salazar-Onfray F, Masucci G, Kiessling R | title = Myeloid-derived suppressor cells impair the quality of dendritic cell vaccines | journal = Cancer Immunology, Immunotherapy | volume = 61 | issue = 6 | pages = 827–838 | date = June 2012 | pmid = 22080405 | doi = 10.1007/s00262-011-1143-y | s2cid = 25043238 | pmc = 11028420 }}

MDSCs are immune suppressive and play a role in tumor maintenance and progression. MDSCs also obstruct therapies that seek to treat cancer through both immunotherapy and other non-immune means.{{Cite journal| vauthors = Ostrand-Rosenberg S |date=2021-03-04|title=Myeloid-Derived Suppressor Cells: Facilitators of Cancer and Obesity-Induced Cancer|journal=Annual Review of Cancer Biology|language=en|volume=5|issue=1|pages=17–38|doi=10.1146/annurev-cancerbio-042120-105240| doi-access=free| issn=2472-3428|hdl=11603/20256|hdl-access=free}}

MDSC activity was originally described as suppressors of T cells, in particular of CD8+ T-cell responses. The spectrum of action of MDSC activity also encompasses NK cells, dendritic cells and macrophages.

Suppressor activity of MDSC is determined by their ability to inhibit the effector function of lymphocytes. Inhibition can be caused by different mechanisms. It is primarily attributed to the effects of the metabolism of L-arginine. Another important factor influencing the activity of MDSC is oppressive ROS.{{cite journal | vauthors = Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI | title = Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species | journal = Journal of Immunology | volume = 172 | issue = 2 | pages = 989–99 | date = January 2004 | pmid = 14707072 | doi = 10.4049/jimmunol.172.2.989 | doi-access = free }}

MDSCs can also play a positive regulatory role. It is stated that MMR vaccine stimulates MDSC populations in people [https://www.sciencedaily.com/releases/2020/06/200619090602.htm taking the vaccine], inhibiting septic inflammation and mortality that is broadly applicable not only to measles, mumps, and rubella, but extends to covid-19 induced cytokine inflammation.{{cite journal |last1=Fidel |first1=Paul L. |last2=Noverr |first2=Mairi C. |title=Could an Unrelated Live Attenuated Vaccine Serve as a Preventive Measure To Dampen Septic Inflammation Associated with COVID-19 Infection? |journal=mBio |date=19 June 2020 |volume=11 |issue=3 |doi=10.1128/mbio.00907-20 |url=https://journals.asm.org/doi/10.1128/mbio.00907-20 |access-date=4 February 2025|pmc=7304316 }} This vaccine stimulation of MDSCs appears to be neither permanent nor chronic. Despite MDSCs being immunosuppressive in certain instances, the MMR vaccine itself is immunostimulatory.

In addition to host-derived factors, pharmacologic agents also have profound impact on MDSC. Chemotherapeutic agents belonging to different classes have been reported to inhibit MDSC. Although this effect may well be secondary to inhibition of hematopoietic progenitors, there may be grounds for search of selectivity based on long-known differential effects of these agents on immunocompetent cells and macrophages. In 2015, MDSCs were compared to immunogenic myeloid cells highlighting a group of core signaling pathways that control pro-carcinogenic MDSC functions.{{cite journal | vauthors = Gato-Cañas M, Martinez de Morentin X, Blanco-Luquin I, Fernandez-Irigoyen J, Zudaire I, Liechtenstein T, Arasanz H, Lozano T, Casares N, Chaikuad A, Knapp S, Guerrero-Setas D, Escors D, Kochan G, Santamaría E | display-authors = 6 | title = A core of kinase-regulated interactomes defines the neoplastic MDSC lineage | journal = Oncotarget | volume = 6 | issue = 29 | pages = 27160–75 | date = September 2015 | pmid = 26320174 | pmc = 4694980 | doi = 10.18632/oncotarget.4746 }}{{Unreliable medical source|date=April 2021}} Many of these pathways are known targets of chemotherapy drugs with strong anti-cancer properties.

{{as of|May 2018}} there are no FDA approved drugs developed to target MDSCs but experimental INB03 has entered early clinical trials.[https://www.clinicalleader.com/doc/inmune-bio-initiates-phase-clinical-trial-of-inb-0001 INmune Bio Initiates Phase I Clinical Trial Of INB03 May 2018]{{cite journal | vauthors = Toor SM, Elkord E | title = Therapeutic prospects of targeting myeloid-derived suppressor cells and immune checkpoints in cancer | journal = Immunology and Cell Biology | volume = 96 | issue = 9 | pages = 888–897 | date = October 2018 | pmid = 29635843 | doi = 10.1111/imcb.12054 | s2cid = 5045808 | doi-access = free }}

There is promising evidence for inhibiting Galectin-3 as a therapeutic target to reduce MDSCs.{{cite journal | vauthors = Wang T, Chu Z, Lin H, Jiang J, Zhou X, Liang X | title = Galectin-3 contributes to cisplatin-induced myeloid derived suppressor cells (MDSCs) recruitment in Lewis lung cancer-bearing mice | journal = Molecular Biology Reports | volume = 41 | issue = 6 | pages = 4069–76 | date = June 2014 | pmid = 24615503 | doi = 10.1007/s11033-014-3276-5 | s2cid = 17451688 }}{{cite journal | vauthors = Blidner AG, Méndez-Huergo SP, Cagnoni AJ, Rabinovich GA | title = Re-wiring regulatory cell networks in immunity by galectin-glycan interactions | journal = FEBS Letters | volume = 589 | issue = 22 | pages = 3407–18 | date = November 2015 | pmid = 26352298 | doi = 10.1016/j.febslet.2015.08.037 | doi-access = free | hdl = 11336/7740 | hdl-access = free }} In a Phase 1b clinical trial of GR-MD-02 developed by Galectin Therapeutics, investigators observed a significant decrease in the frequency of suppressive myeloid-derived suppressor cells following treatment in responding melanoma patients.{{cite press release |url=http://www.globenewswire.com/news-release/2018/09/20/1573647/0/en/Galectin-Therapeutics-Inc-Announces-Positive-Preliminary-Results-from-Phase-1b-Clinical-Trial-of-GR-MD-02-and-KEYTRUDA-in-Advanced-Melanoma-and-Expansion-of-the-Trial.html |title=Positive Preliminary Results from Phase 1b Clinical Trial of GR-MD-02 and KEYTRUDA® in Advanced Melanoma and Expansion of the Trial | author = Galectin Therapeutics Inc. |date=2018-09-20 |website= GlobeNewswire News Room |access-date=2019-03-14 }}

The term myeloid-derived suppressor cell originated in a 2007 journal article published in Cancer Research by Gabrilovich et al. Publications in 2008 established that there are two subpopulations of MDSC: mononuclear MDSC (M-MDSC) and polymorphonuclear or granulocytic MDSC (PMN-MDSC). M-MDSC are similar to monocytes found in blood, while PMN-MDSC are physically akin to neutrophils.

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Category:Cell biology