The role of myeloid-derived suppressor cells in glioma microenvironment_Journal of Biomedical Engineering

Authors：

GAO Ce ,  WANG Aidong

Experimental Center of the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R.China;

Corresponding author：

Keywords：

glioma microenvironment; immunosuppression; myeloid-derived suppressor cells

DOI：

10.7507/1001-5515.201806045

Video：

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Glioma is one of the most common primary tumors in the human brain with poor prognosis. The local and systemic immunosuppressive environment created by glioma cells enables them to evade immunosurveillance. Myeloid-derived suppressor cells (MDSCs) are a critical component of the immunosuppression system. They are a heterogeneous cell population composed of early myeloid progenitor cells and precursor cells. Although the cells are diverse in phenotypes and functions, they all have strong immunosuppressive functions. MDSCs are extensively infiltrated into tumor tissues and play an important role in the glioma immunosuppressive microenvironment, which also hinders the immunotherapeutic effects of glioma. This article will review the phenotypic characteristics of MDSCs in the glioma microenvironment and their role in the progression of glioma. It is of positive significance to better understand the pathogenesis of glioma and explore effective comprehensive treatments.

Citation： GAO Ce, WANG Aidong. The role of myeloid-derived suppressor cells in glioma microenvironment. Journal of Biomedical Engineering, 2019, 36(3): 515-520. doi: 10.7507/1001-5515.201806045 Copy

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2.	Klemm F, Joyce J A. Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol, 2015, 25(4): 198-213.
3.	Kumar V, Patel S, Tcyganov E, et al. The Nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol, 2016, 37(3): 208-220.
4.	Gieryng A, Pszczolkowska D, Walentynowicz K A, et al. Immune microenvironment of gliomas. Laboratory Investigation, 2017, 97(5): 498-518.
5.	Mieczkowski J, Kocyk M, Nauman P, et al. Down-regulation of IKKβ expression in glioma-infltrating microglia/macrophages is associated with defective in?ammatory/immune gene responses in glioblastoma. Oncotarget, 2015, 6(32): 33077-33090.
6.	Szulzewsky F, Arora S, de Witte L, et al. Human glioblastoma-associated microglia/monocytes express a distinct RNA profle compared to human control and murine samples. Glia, 2016, 64(8): 1416-1436.
7.	Pyonteck S M, Akkari L, Schuhmacher A J, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med, 2013, 19(10): 1264-1272.
8.	Zhao Aimin, Xu Haijing, Kang Xiaomin, et al. New insights into myeloid-derived suppressor cells and their roles in feto-maternal immune cross-talk. J Reprod Immunol, 2016, 113: 35-41.
9.	Gielen P R, Schulte B M, Kers-Rebel E D, et al. Increase in both CD14-Positive and CD15-Positive Myeloid-Derived suppressor cell subpopulations in the blood of patients with glioma but predominance of CD15-Positive myeloid-derived suppressor cells in glioma tissue. J Neuropathol Exp Neurol, 2015, 74(5): 390-400.
10.	Gielen P R, Schulte B M, Kers-Rebel E D, et al. Elevated levels of polymorphonuclear myeloid-derived suppressor cells in patients with glioblastoma highly Express S100A8/9 and arginase and suppress T cell function. Neuro Oncol, 2016, 18(9): 1253-1264.
11.	Abad C, Nobuta H, LI J, et al. Targeted STAT3 disruption in myeloid cells alters immunosuppressor cell abundance in a murine model of spontaneous medulloblastoma. J Leukoc Biol, 2014, 95(2): 357-367.
12.	Mao Yumeng, Poschke I, Wennerberg E, et al. Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms. Cancer Res, 2013, 73(13): 3877-3887.
13.	Cheng P, Corzo C A, Luetteke N, et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med, 2008, 205(10): 2235-2249.
14.	Heimberger A B, Abou-Ghazal M, Reina-Ortiz C A, et al. Incidence and prognostic impact of FoxP3(+) regulatory T cells in human gliomas. Clinical Cancer Research, 2008, 14(16): 5166-5172.
15.	Maes W, Verschuere T, van Hoylandt A, et al. Depletion of regulatory T cells in a mouse experimental glioma model through anti-CD25 treatment results in the infiltration of non-immunosuppressive myeloid cells in the brain. Clin Dev Immunol, 2013, 2013: 952469.
16.	Sampson J H, Schmittling R J, Archer G E, et al. A pilot study of IL-2R alpha blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma. PLoS One, 2012, 7(2): e31046.
17.	Kmiecik J, Poli A, Brons N H, et al. Elevated CD3(+) and CD8(+) tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level. J Neuroimmunol, 2013, 264(1/2): 71-83.
18.	Mu Luyan, Yang Changlin, Gao Qiang, et al. CD4+and perivascular Foxp3+ T cells in glioma correlate with angiogenesis and tumor progression. Front Immunol, 2017, 8: 1451.
19.	Baker G J, Chockley P, Zamler D, et al. Natural killer cells require monocytic Gr-1(+)/CD11b(+) myeloid cells to eradicate orthotopically engrafted glioma cells. Oncoimmunology, 2016, 5(6): e1163461.
20.	Chang A L, Miska J, Wainwright D A, et al. CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Cancer Res, 2016, 76(19): 5671-5682.
21.	Kjellman C, Olofsson S P, Hansson O, et al. Expression of TGF-beta isoforms, TGF-beta receptors, and SMAD molecules at different stages of human glioma. Int J Cancer, 2000, 89(3): 251-258.
22.	Qi Ling, Yu Hongquan, Zhang Yu, et al. IL-10 secreted by M2 macrophage promoted tumorigenesis through interaction with JAK2 in glioma. Oncotarget, 2016, 7(44): 71673-71685.
23.	Rodrigues J C, Gonzalez G C, Zhang L, et al. Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro Oncol, 2010, 12(4): 351-365.
24.	Cantini G, Pisati F, Mastropietro A A, et al. A critical role for regulatory T cells in driving cytokine profiles of Th17 cells and their modulation of glioma microenvironment. Cancer Immunology Immunotherapy, 2011, 60(12): 1739-1750.
25.	Otvos B, Silver D J, Mulkearns-Hubert E E, et al. Cancer stem cell-secreted macrophage migration inhibitory factor stimulates myeloid derived suppressor cell function and facilitates glioblastoma immune evasion. Stem Cells, 2016, 34(8): 2026-2039.
26.	Wintterle S, Schreiner B, Mitsdoerffer M, et al. Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res, 2003, 63(21): 7462-7467.
27.	Kohanbash G, Mckaveney K, Sakaki M, et al. GM-CSF promotes the immunosuppressive activity of glioma-infiltrating myeloid cells through interleukin-4 receptor-alpha. Cancer Res, 2013, 73(21): 6413-6423.
28.	Pillay J, Tak T, Kamp V M, et al. Immune suppression by neutrophils and granulocytic myeloid-derived suppressor cells: similarities and differences. Cellular and Molecular Life Sciences, 2013, 70(20): 3813-3827.
29.	Leroi N, Lallemand F, Coucke P, et al. Impacts of ionizing radiation on the different compartments of the tumor microenvironment. Front Pharmacol, 2016, 7: 78.
30.	Bronte V, Brandau S, Chen S H, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun, 2016, 7: 12150.
31.	Youn J I, Gabrilovich D I. The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol, 2010, 40(11): 2969-2975.
32.	Kumar R, de Mooij T, Peterson T, et al. Modulating glioma-mediated myeloid-derived suppressor cell development with sulforaphane. Neuro Oncol, 2016, 18(6): 99-100.
33.	Raychaudhuri B, Rayman P, Ireland J, et al. Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma. Neuro Oncol, 2011, 13(6): 591-599.
34.	Dubinski D, Wölfer J, Hasselblatt M, et al. CD4+T effector memory cell dysfunction is associated with the accumulation of granulocytic myeloid-derived suppressor cells in glioblastoma patients. Neuro Oncol, 2016, 18(6): 807-818.
35.	Raychaudhuri B, Rayman P, Huang P A, et al. Myeloid derived suppressor cell infiltration of murine and human gliomas is associated with reduction of tumor infiltrating lymphocytes. J Neurooncol, 2015, 122(2): 293-301.
36.	Chae M, Peterson T E, Balgeman A, et al. Increasing glioma-associated monocytes leads to increased intratumoral and systemic myeloid-derived suppressor cells in a murine model. Neuro Oncol, 2015, 17(7): 978-991.
37.	Fujita M, Kohanbash G, Fellows-Mayle W, et al. COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells. Cancer Res, 2011, 71(7): 2664-2674.
38.	Verschuere T, Toelen J, Maes W, et al. Glioma-derived galectin-1 regulates innate and adaptive antitumor immunity. International Journal of Cancer, 2014, 134(4): 873-884.
39.	Zhang Y, Luo F, Li A, et al. Systemic injection of TLR1/2 agonist improves adoptive antigen-specific T cell therapy in glioma-bearing mice. Clin Immunol, 2014, 154(1): 26-36.
40.	Zhu Xinmei, Fujita M, Snyder L A, et al. Systemic delivery of neutralizing antibody targeting CCL2 for glioma therapy. J Neurooncol, 2011, 104(1): 83-92.
41.	Kamran N, Kadiyala P, Saxena M, et al. Immunosuppressive myeloid cells' blockade in the glioma microenvironment enhances the efficacy of immune-stimulatory gene therapy. Mol Ther, 2017, 25(1): 232-248.

1. Dolecek T A, Propp J M, Stroup N E, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro Oncol, 2012, 14(Suppl 5): v1-v49.
2. Klemm F, Joyce J A. Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol, 2015, 25(4): 198-213.
3. Kumar V, Patel S, Tcyganov E, et al. The Nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol, 2016, 37(3): 208-220.
4. Gieryng A, Pszczolkowska D, Walentynowicz K A, et al. Immune microenvironment of gliomas. Laboratory Investigation, 2017, 97(5): 498-518.
5. Mieczkowski J, Kocyk M, Nauman P, et al. Down-regulation of IKKβ expression in glioma-infltrating microglia/macrophages is associated with defective in?ammatory/immune gene responses in glioblastoma. Oncotarget, 2015, 6(32): 33077-33090.
6. Szulzewsky F, Arora S, de Witte L, et al. Human glioblastoma-associated microglia/monocytes express a distinct RNA profle compared to human control and murine samples. Glia, 2016, 64(8): 1416-1436.
7. Pyonteck S M, Akkari L, Schuhmacher A J, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med, 2013, 19(10): 1264-1272.
8. Zhao Aimin, Xu Haijing, Kang Xiaomin, et al. New insights into myeloid-derived suppressor cells and their roles in feto-maternal immune cross-talk. J Reprod Immunol, 2016, 113: 35-41.
9. Gielen P R, Schulte B M, Kers-Rebel E D, et al. Increase in both CD14-Positive and CD15-Positive Myeloid-Derived suppressor cell subpopulations in the blood of patients with glioma but predominance of CD15-Positive myeloid-derived suppressor cells in glioma tissue. J Neuropathol Exp Neurol, 2015, 74(5): 390-400.
10. Gielen P R, Schulte B M, Kers-Rebel E D, et al. Elevated levels of polymorphonuclear myeloid-derived suppressor cells in patients with glioblastoma highly Express S100A8/9 and arginase and suppress T cell function. Neuro Oncol, 2016, 18(9): 1253-1264.
11. Abad C, Nobuta H, LI J, et al. Targeted STAT3 disruption in myeloid cells alters immunosuppressor cell abundance in a murine model of spontaneous medulloblastoma. J Leukoc Biol, 2014, 95(2): 357-367.
12. Mao Yumeng, Poschke I, Wennerberg E, et al. Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms. Cancer Res, 2013, 73(13): 3877-3887.
13. Cheng P, Corzo C A, Luetteke N, et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med, 2008, 205(10): 2235-2249.
14. Heimberger A B, Abou-Ghazal M, Reina-Ortiz C A, et al. Incidence and prognostic impact of FoxP3(+) regulatory T cells in human gliomas. Clinical Cancer Research, 2008, 14(16): 5166-5172.
15. Maes W, Verschuere T, van Hoylandt A, et al. Depletion of regulatory T cells in a mouse experimental glioma model through anti-CD25 treatment results in the infiltration of non-immunosuppressive myeloid cells in the brain. Clin Dev Immunol, 2013, 2013: 952469.
16. Sampson J H, Schmittling R J, Archer G E, et al. A pilot study of IL-2R alpha blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma. PLoS One, 2012, 7(2): e31046.
17. Kmiecik J, Poli A, Brons N H, et al. Elevated CD3(+) and CD8(+) tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level. J Neuroimmunol, 2013, 264(1/2): 71-83.
18. Mu Luyan, Yang Changlin, Gao Qiang, et al. CD4+and perivascular Foxp3+ T cells in glioma correlate with angiogenesis and tumor progression. Front Immunol, 2017, 8: 1451.
19. Baker G J, Chockley P, Zamler D, et al. Natural killer cells require monocytic Gr-1(+)/CD11b(+) myeloid cells to eradicate orthotopically engrafted glioma cells. Oncoimmunology, 2016, 5(6): e1163461.
20. Chang A L, Miska J, Wainwright D A, et al. CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Cancer Res, 2016, 76(19): 5671-5682.
21. Kjellman C, Olofsson S P, Hansson O, et al. Expression of TGF-beta isoforms, TGF-beta receptors, and SMAD molecules at different stages of human glioma. Int J Cancer, 2000, 89(3): 251-258.
22. Qi Ling, Yu Hongquan, Zhang Yu, et al. IL-10 secreted by M2 macrophage promoted tumorigenesis through interaction with JAK2 in glioma. Oncotarget, 2016, 7(44): 71673-71685.
23. Rodrigues J C, Gonzalez G C, Zhang L, et al. Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro Oncol, 2010, 12(4): 351-365.
24. Cantini G, Pisati F, Mastropietro A A, et al. A critical role for regulatory T cells in driving cytokine profiles of Th17 cells and their modulation of glioma microenvironment. Cancer Immunology Immunotherapy, 2011, 60(12): 1739-1750.
25. Otvos B, Silver D J, Mulkearns-Hubert E E, et al. Cancer stem cell-secreted macrophage migration inhibitory factor stimulates myeloid derived suppressor cell function and facilitates glioblastoma immune evasion. Stem Cells, 2016, 34(8): 2026-2039.
26. Wintterle S, Schreiner B, Mitsdoerffer M, et al. Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res, 2003, 63(21): 7462-7467.
27. Kohanbash G, Mckaveney K, Sakaki M, et al. GM-CSF promotes the immunosuppressive activity of glioma-infiltrating myeloid cells through interleukin-4 receptor-alpha. Cancer Res, 2013, 73(21): 6413-6423.
28. Pillay J, Tak T, Kamp V M, et al. Immune suppression by neutrophils and granulocytic myeloid-derived suppressor cells: similarities and differences. Cellular and Molecular Life Sciences, 2013, 70(20): 3813-3827.
29. Leroi N, Lallemand F, Coucke P, et al. Impacts of ionizing radiation on the different compartments of the tumor microenvironment. Front Pharmacol, 2016, 7: 78.
30. Bronte V, Brandau S, Chen S H, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun, 2016, 7: 12150.
31. Youn J I, Gabrilovich D I. The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity. Eur J Immunol, 2010, 40(11): 2969-2975.
32. Kumar R, de Mooij T, Peterson T, et al. Modulating glioma-mediated myeloid-derived suppressor cell development with sulforaphane. Neuro Oncol, 2016, 18(6): 99-100.
33. Raychaudhuri B, Rayman P, Ireland J, et al. Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma. Neuro Oncol, 2011, 13(6): 591-599.
34. Dubinski D, Wölfer J, Hasselblatt M, et al. CD4+T effector memory cell dysfunction is associated with the accumulation of granulocytic myeloid-derived suppressor cells in glioblastoma patients. Neuro Oncol, 2016, 18(6): 807-818.
35. Raychaudhuri B, Rayman P, Huang P A, et al. Myeloid derived suppressor cell infiltration of murine and human gliomas is associated with reduction of tumor infiltrating lymphocytes. J Neurooncol, 2015, 122(2): 293-301.
36. Chae M, Peterson T E, Balgeman A, et al. Increasing glioma-associated monocytes leads to increased intratumoral and systemic myeloid-derived suppressor cells in a murine model. Neuro Oncol, 2015, 17(7): 978-991.
37. Fujita M, Kohanbash G, Fellows-Mayle W, et al. COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells. Cancer Res, 2011, 71(7): 2664-2674.
38. Verschuere T, Toelen J, Maes W, et al. Glioma-derived galectin-1 regulates innate and adaptive antitumor immunity. International Journal of Cancer, 2014, 134(4): 873-884.
39. Zhang Y, Luo F, Li A, et al. Systemic injection of TLR1/2 agonist improves adoptive antigen-specific T cell therapy in glioma-bearing mice. Clin Immunol, 2014, 154(1): 26-36.
40. Zhu Xinmei, Fujita M, Snyder L A, et al. Systemic delivery of neutralizing antibody targeting CCL2 for glioma therapy. J Neurooncol, 2011, 104(1): 83-92.
41. Kamran N, Kadiyala P, Saxena M, et al. Immunosuppressive myeloid cells' blockade in the glioma microenvironment enhances the efficacy of immune-stimulatory gene therapy. Mol Ther, 2017, 25(1): 232-248.

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