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Myeloid-derived suppressor cell

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Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immune cells from the myeloid lineage (a family of cells that originate from bone marrow stem cells).

MDSCs expand under pathologic conditions such as chronic infection and cancer, as a result of altered haematopoiesis.[1] MDSCs differ from other myeloid cell types in that they have immunosuppressive activities, as opposed to immune-stimulatory properties. Similar to other myeloid cells, MDSCs interact with immune cell types such as T cells, dendritic cells, macrophages and natural killer cells to regulate their functions. Tumors with high levels of infiltration by MDSCs have been associated with poor patient outcome and resistance to therapies.[2][3][4][5] MDSCs can also be detected in the blood. In patients with breast cancer, levels of MDSC in blood are about 10-fold higher than normal.[6] The size of the myeloid suppressor compartment is considered to be an important factor in the success or failure of cancer immunotherapy, highlighting the importance of this cell type for human pathophysiology.[7] A high level of MDSC infiltrate in the tumor microenvironment correlates with shorter survival times of patients with solid tumors and could mediate resistance to checkpoint inhibitor therapy.[8] Studies are needed to determine whether MDSCs are a population of immature myeloid cells that have stopped differentiation or a distinct myeloid lineage.

Formation

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MDSCs are formed from bone marrow precursors when myelopoietic processes are interrupted, caused by several illnesses.[9][10] 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 IL6, which promote development of MDSCs that have immune suppressive function in vivo. Other cytokines, including IL10, 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.[11]

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, TGFB, and 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.[12] 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.

Immature Myeloid Cells in Formation of MDSCs

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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 especial 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.[13][14][15]

However, a recent research of the University of Salamanca has demonstrated that immature myeloid cells (IMCs), the precursosrs of MDSCs, have also potential immunosuppressive activity under pathological conditions.[16] 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.[17]

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.[18] 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.

MDSC differentiation

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In humans

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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.[2][19] The myeloid-differentiation cytokine GM-CSF is a key factor in MDSC production from bone marrow,[20][unreliable medical source?] 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.

In mice

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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.[20][21] This differentiation process is accelerated upon tumor infiltration and possibly driven by the hypoxic tumor microenvironment.

Phenotype

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Natural killer cells

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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.[22] 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.[23]

B cells

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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).[24]

Dendritic cells

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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.[25][26]

Activity/function

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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.[27] 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.[2][28]

Effect of MMR vaccination

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MDSCs can also play a positive regulatory role. It is stated that MMR vaccine stimulates MDSC populations in people 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.[citation needed] This vaccination inducement appears to be neither permanent nor chronic.[clarification needed] Despite MDSC's being immunosuppressive in certain instances, the MMR vaccine itself is immunostimulatory.

MDSC inhibitors

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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.[2] In 2015, MDSCs were compared to immunogenic myeloid cells highlighting a group of core signaling pathways that control pro-carcinogenic MDSC functions.[29][unreliable medical source?] 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.[30][31]

There is promising evidence for inhibiting Galectin-3 as a therapeutic target to reduce MDSCs.[32][33] 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.[34]

History

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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.[27]

References

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  1. ^ Li T, Li X, Chen YH (May 2020). "c-Rel is a myeloid checkpoint for cancer immunotherapy". Nature Cancer. 1 (5): 507–517. doi:10.1038/s43018-020-0061-3. PMC 7808269. PMID 33458695.
  2. ^ a b c d Mantovani A (December 2010). "The growing diversity and spectrum of action of myeloid-derived suppressor cells". European Journal of Immunology. 40 (12): 3317–20. doi:10.1002/eji.201041170. PMID 21110315.
  3. ^ Allavena P, Mantovani A (February 2012). "Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment". Clinical and Experimental Immunology. 167 (2): 195–205. doi:10.1111/j.1365-2249.2011.04515.x. PMC 3278685. PMID 22235995.
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  19. ^ Gros A, Turcotte S, Wunderlich JR, Ahmadzadeh M, Dudley ME, Rosenberg SA (October 2012). "Myeloid cells obtained from the blood but not from the tumor can suppress T-cell proliferation in patients with melanoma". Clinical Cancer Research. 18 (19): 5212–23. doi:10.1158/1078-0432.CCR-12-1108. PMC 6374773. PMID 22837179.
  20. ^ a b Liechtenstein T, Perez-Janices N, Gato M, Caliendo F, Kochan G, Blanco-Luquin I, et al. (September 2014). "A highly efficient tumor-infiltrating MDSC differentiation system for discovery of anti-neoplastic targets, which circumvents the need for tumor establishment in mice". Oncotarget. 5 (17): 7843–57. doi:10.18632/oncotarget.2279. PMC 4202165. PMID 25151659.
  21. ^ Youn JI, Kumar V, Collazo M, Nefedova Y, Condamine T, Cheng P, et al. (March 2013). "Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer". Nature Immunology. 14 (3): 211–20. doi:10.1038/ni.2526. PMC 3578019. PMID 23354483.
  22. ^ Zhao Y, Wu T, Shao S, Shi B, Zhao Y (February 2016). "Phenotype, development, and biological function of myeloid-derived suppressor cells". Oncoimmunology. 5 (2): e1004983. doi:10.1080/2162402x.2015.1004983. PMC 4801459. PMID 27057424.
  23. ^ Engwerda C (2013-04-26). "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. {{cite journal}}: Cite journal requires |journal= (help)
  24. ^ Green KA, Cook WJ, Green WR (February 2013). "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 of Virology. 87 (4): 2058–2071. doi:10.1128/jvi.01547-12. PMC 3571497. PMID 23221564.
  25. ^ Greifenberg V, Ribechini E, Rössner S, Lutz MB (October 2009). "Myeloid-derived suppressor cell activation by combined LPS and IFN-gamma treatment impairs DC development". European Journal of Immunology. 39 (10): 2865–2876. doi:10.1002/eji.200939486. PMID 19637228. S2CID 26342683.
  26. ^ Poschke I, Mao Y, Adamson L, Salazar-Onfray F, Masucci G, Kiessling R (June 2012). "Myeloid-derived suppressor cells impair the quality of dendritic cell vaccines". Cancer Immunology, Immunotherapy. 61 (6): 827–838. doi:10.1007/s00262-011-1143-y. PMC 11028420. PMID 22080405. S2CID 25043238.
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  28. ^ Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI (January 2004). "Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species". Journal of Immunology. 172 (2): 989–99. doi:10.4049/jimmunol.172.2.989. PMID 14707072.
  29. ^ Gato-Cañas M, Martinez de Morentin X, Blanco-Luquin I, Fernandez-Irigoyen J, Zudaire I, Liechtenstein T, et al. (September 2015). "A core of kinase-regulated interactomes defines the neoplastic MDSC lineage". Oncotarget. 6 (29): 27160–75. doi:10.18632/oncotarget.4746. PMC 4694980. PMID 26320174.
  30. ^ INmune Bio Initiates Phase I Clinical Trial Of INB03 May 2018
  31. ^ Toor SM, Elkord E (October 2018). "Therapeutic prospects of targeting myeloid-derived suppressor cells and immune checkpoints in cancer". Immunology and Cell Biology. 96 (9): 888–897. doi:10.1111/imcb.12054. PMID 29635843. S2CID 5045808.
  32. ^ Wang T, Chu Z, Lin H, Jiang J, Zhou X, Liang X (June 2014). "Galectin-3 contributes to cisplatin-induced myeloid derived suppressor cells (MDSCs) recruitment in Lewis lung cancer-bearing mice". Molecular Biology Reports. 41 (6): 4069–76. doi:10.1007/s11033-014-3276-5. PMID 24615503. S2CID 17451688.
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  34. ^ Galectin Therapeutics Inc. (2018-09-20). "Positive Preliminary Results from Phase 1b Clinical Trial of GR-MD-02 and KEYTRUDA® in Advanced Melanoma and Expansion of the Trial". GlobeNewswire News Room (Press release). Retrieved 2019-03-14.
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