1. Please check and comment entries here.
Table of Contents

    Topic review

    Myeloid-Derived Suppressor Cells in HGG

    Subjects: Cell Biology
    View times: 37

    Definition

    The immune microenvironment of high-grade gliomas (HGG) is a complex and heterogeneous system, consisting of diverse cell types such as microglia, bone marrow-derived macrophages (BMDMs), myeloid-derived suppressor cells (MDSCs), dendritic cells, natural killer (NK) cells, and T-cells. Of these, MDSCs are one of the major tumor-infiltrating immune cells and are correlated not only with overall worse prognosis but also poor clinical outcomes. Upon entry from the bone marrow into the peripheral blood, spleen, as well as in tumor microenvironment (TME) in HGG patients, MDSCs deploy an array of mechanisms to perform their immune and non-immune suppressive functions. 

    1. Introduction

    Extensive analysis of the immune microenvironment in high-grade glioma (HGG) using single-cell RNA-seq, mass cytometry (CyTOF), immunohistochemistry, flow cytometry, and other “omics” technologies indicate the presence of higher numbers of immune-suppressive macrophages, microglia dendritic cells, regulatory T-cells, and myeloid-derived suppressor cells (MDSCs) [1]. Together, these cells interact with the neoplastic cells to promote tumor growth, progression, metastasis, angiogenesis and contribute to the extreme immunosuppression observed in HGG.

    In healthy humans and mice, MDSCs are present at very low frequencies and constitute only ~0.5–2% of peripheral blood mononuclear cells [2]. Nevertheless, 30–50% of the tumor mass in HGGs are found to be MDSCs [3][4]. Originally, derived from the bone marrow, MDSCs are a very heterogeneous population of immature myeloid cells (IMCs) present at various stages of myelopoiesis. Under normal conditions, IMCs can be differentiated into macrophages, granulocytes, and dendritic cells. However, in pathological conditions such as HGG, the differentiation of IMCs is subverted, resulting in the generation, recruitment, expansion, and activation of MDSCs [5] not only in the tumor bed but also in the peripheral blood [6][7].

    2. History of MDSCs

    In HGGs, MDSCs are derived from the immature myeloid progenitors present in the bone marrow (Figure 1). More recently, single-cell RNA-sequencing (scRNA-seq) analysis on mouse breast tumors suggests that abnormal differentiation of monocyte and neutrophil-like cells in the spleen can lead to the generation of MDSCs [8]. Reprogramming or activation of monocytes and granulocytes by exposure to Toll-like receptors, IL-10, WNT5A, LPS, and INFγ can also give rise to MDSCs [9]. Lastly, MDSCs can be generated and activated ex vivo by the addition of GM-CSF, G-CSF, IL-6, and IL-10 to bone marrow precursors obtained from healthy individuals and detailed functional and phenotypic characterization revealed these bone marrow-derived MDSCs (BM-MDSCs) to be similar to the MDSCs present in different cancer patients [10][11].

    This entry is adapted from 10.3390/cells10040893

    References

    1. Fu, W.; Wang, W.; Li, H.; Jiao, Y.; Huo, R.; Yan, Z.; Wang, J.; Wang, S.; Wang, J.; Chen, D.; et al. Single-Cell Atlas Reveals Complexity of the Immunosuppressive Microenvironment of Initial and Recurrent Glioblastoma. Front. Immunol. 2020, 11, 835.
    2. Almand, B.; Clark, J.I.; Nikitina, E.; van Beynen, J.; English, N.R.; Knight, S.C.; Carbone, D.P.; Gabrilovich, D.I. Increased production of immature myeloid cells in cancer patients: A mechanism of immunosuppression in cancer. J. Immunol. 2001, 166, 678–689.
    3. Kamran, N.; Kadiyala, P.; Saxena, M.; Candolfi, M.; Li, Y.; Moreno-Ayala, M.A.; Raja, N.; Shah, D.; Lowenstein, P.R.; Castro, M.G. Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy. Mol. Ther. 2017, 25, 232–248.
    4. Gabrusiewicz, K.; Rodriguez, B.; Wei, J.; Hashimoto, Y.; Healy, L.M.; Maiti, S.N.; Thomas, G.; Zhou, S.; Wang, Q.; Elakkad, A.; et al. Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype. JCI Insight 2016, 1, e85841.
    5. Gabrilovich, D.I.; Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 2009, 9, 162–174.
    6. Yamauchi, Y.; Safi, S.; Blattner, C.; Rathinasamy, A.; Umansky, L.; Juenger, S.; Warth, A.; Eichhorn, M.; Muley, T.; Herth, F.J.F.; et al. Circulating and Tumor Myeloid-derived Suppressor Cells in Resectable Non-Small Cell Lung Cancer. Am. J. Respir. Crit. Care Med. 2018, 198, 777–787.
    7. Kumar, V.; Patel, S.; Tcyganov, E.; Gabrilovich, D.I. The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. Trends Immunol. 2016, 37, 208–220.
    8. Alshetaiwi, H.; Pervolarakis, N.; McIntyre, L.L.; Ma, D.; Nguyen, Q.; Rath, J.A.; Nee, K.; Hernandez, G.; Evans, K.; Torosian, L.; et al. Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics. Sci. Immunol. 2020, 5, e6017.
    9. Millrud, C.R.; Bergenfelz, C.; Leandersson, K. On the origin of myeloid-derived suppressor cells. Oncotarget 2017, 8, 3649–3665.
    10. Solito, S.; Falisi, E.; Diaz-Montero, C.M.; Doni, A.; Pinton, L.; Rosato, A.; Francescato, S.; Basso, G.; Zanovello, P.; Onicescu, G.; et al. A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood 2011, 118, 2254–2265.
    11. Heine, A.; Held, S.A.E.; Schulte-Schrepping, J.; Wolff, J.F.A.; Klee, K.; Ulas, T.; Schmacke, N.A.; Daecke, S.N.; Riethausen, K.; Schultze, J.L.; et al. Generation and functional characterization of MDSC-like cells. Oncoimmunology 2017, 6, e1295203.
    12. Kohanbash, G.; Okada, H. Myeloid-derived suppressor cells (MDSCs) in gliomas and glioma-development. Immunol. Investig. 2012, 41, 658–679.
    13. Zhu, X.; Fujita, M.; Snyder, L.A.; Okada, H. Systemic delivery of neutralizing antibody targeting CCL2 for glioma therapy. J. Neurooncol. 2011, 104, 83–92.
    14. Alban, T.J.; Alvarado, A.G.; Sorensen, M.D.; Bayik, D.; Volovetz, J.; Serbinowski, E.; Mulkearns-Hubert, E.E.; Sinyuk, M.; Hale, J.S.; Onzi, G.R.; et al. Global immune fingerprinting in glioblastoma patient peripheral blood reveals immune-suppression signatures associated with prognosis. JCI Insight 2018, 3.
    15. Moertel, C.L.; Xia, J.; LaRue, R.; Waldron, N.N.; Andersen, B.M.; Prins, R.M.; Okada, H.; Donson, A.M.; Foreman, N.K.; Hunt, M.A.; et al. CD200 in CNS tumor-induced immunosuppression: The role for CD200 pathway blockade in targeted immunotherapy. J. Immunother. Cancer 2014, 2, 46.
    16. Zhai, L.; Ladomersky, E.; Lauing, K.L.; Wu, M.; Genet, M.; Gritsina, G.; Gyorffy, B.; Brastianos, P.K.; Binder, D.C.; Sosman, J.A.; et al. Infiltrating T Cells Increase IDO1 Expression in Glioblastoma and Contribute to Decreased Patient Survival. Clin. Cancer Res. 2017, 23, 6650–6660.
    17. Chang, A.L.; Miska, J.; Wainwright, D.A.; Dey, M.; Rivetta, C.V.; Yu, D.; Kanojia, D.; Pituch, K.C.; Qiao, J.; Pytel, P.; 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, 5671–5682.
    18. Alban, T.J.; Bayik, D.; Otvos, B.; Rabljenovic, A.; Leng, L.; Jia-Shiun, L.; Roversi, G.; Lauko, A.; Momin, A.A.; Mohammadi, A.M.; et al. Glioblastoma Myeloid-Derived Suppressor Cell Subsets Express Differential Macrophage Migration Inhibitory Factor Receptor Profiles That Can Be Targeted to Reduce Immune Suppression. Front. Immunol. 2020, 11, 1191.
    19. Chiu, D.K.C.; Tse, A.P.W.; Xu, I.M.J.; Di Cui, J.; Lai, R.K.H.; Li, L.L.; Koh, H.Y.; Tsang, F.H.C.; Wei, L.L.; Wong, C.M.; et al. Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma. Nat. Commun. 2017, 8, 1–12.
    20. Chiu, D.K.C.; Xu, I.M.J.; Lai, R.K.H.; Tse, A.P.W.; Wei, L.L.; Koh, H.Y.; Li, L.L.; Lee, D.; Lo, R.C.L.; Wong, C.M.; et al. Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26. Hepatology 2016, 64, 797–813.
    21. Corzo, C.A.; Condamine, T.; Lu, L.; Cotter, M.J.; Youn, J.I.; Cheng, P.; Cho, H.I.; Celis, E.; Quiceno, D.G.; Padhya, T.; et al. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J. Exp. Med. 2010, 207, 2439–2453.
    22. De Leo, A.; Ugolini, A.; Veglia, F. Myeloid Cells in Glioblastoma Microenvironment. Cells 2020, 10, 18.
    23. Yan, D.; Adeshakin, A.O.; Xu, M.; Afolabi, L.O.; Zhang, G.; Chen, Y.H.; Wan, X. Lipid Metabolic Pathways Confer the Immunosuppressive Function of Myeloid-Derived Suppressor Cells in Tumor. Front. Immunol. 2019, 10, 1399.
    24. Raychaudhuri, B.; Rayman, P.; Ireland, J.; Ko, J.; Rini, B.; Borden, E.C.; Garcia, J.; Vogelbaum, M.A.; Finke, J. Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma. Neuro. Oncol. 2011, 13, 591–599.
    25. Gielen, P.R.; Schulte, B.M.; Kers-Rebel, E.D.; Verrijp, K.; Bossman, S.A.; Ter Laan, M.; Wesseling, P.; Adema, G.J. 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, 1253–1264.
    26. Lindau, D.; Gielen, P.; Kroesen, M.; Wesseling, P.; Adema, G.J. The immunosuppressive tumour network: Myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology 2013, 138, 105–115.
    27. Wan, Y.Y. Regulatory T cells: Immune suppression and beyond. Cell Mol. Immunol. 2010, 7, 204–210.
    28. Li, H.; Han, Y.; Guo, Q.; Zhang, M.; Cao, X. Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J. Immunol. 2009, 182, 240–249.
    29. Tao, J.; Han, D.; Gao, S.; Zhang, W.; Yu, H.; Liu, P.; Fu, R.; Li, L.; Shao, Z. CD8(+) T cells exhaustion induced by myeloid-derived suppressor cells in myelodysplastic syndromes patients might be through TIM3/Gal-9 pathway. J. Cell Mol. Med. 2020, 24, 1046–1058.
    30. Hou, A.; Hou, K.; Huang, Q.; Lei, Y.; Chen, W. Targeting Myeloid-Derived Suppressor Cell, a Promising Strategy to Overcome Resistance to Immune Checkpoint Inhibitors. Front. Immunol. 2020, 11, 783.
    31. Clavijo, P.E.; Moore, E.C.; Chen, J.; Davis, R.J.; Friedman, J.; Kim, Y.; Van Waes, C.; Chen, Z.; Allen, C.T. Resistance to CTLA-4 checkpoint inhibition reversed through selective elimination of granulocytic myeloid cells. Oncotarget 2017, 8, 55804–55820.
    32. Weber, R.; Fleming, V.; Hu, X.; Nagibin, V.; Groth, C.; Altevogt, P.; Utikal, J.; Umansky, V. Myeloid-Derived Suppressor Cells Hinder the Anti-Cancer Activity of Immune Checkpoint Inhibitors. Front. Immunol. 2018, 9, 1310.
    33. Ramachandran, C.; Nair, S.M.; Escalon, E.; Melnick, S.J. Potentiation of etoposide and temozolomide cytotoxicity by curcumin and turmeric force™ in brain tumor cell lines. J. Complement Integr. Med. 2012, 9.
    34. Gersey, Z.C.; Rodriguez, G.A.; Barbarite, E.; Sanchez, A.; Walters, W.M.; Ohaeto, K.C.; Komotar, R.J.; Graham, R.M. Curcumin decreases malignant characteristics of glioblastoma stem cells via induction of reactive oxygen species. BMC Cancer 2017, 17, 99.
    35. Peak, T.C.; Richman, A.; Gur, S.; Yafi, F.A.; Hellstrom, W.J. The Role of PDE5 Inhibitors and the NO/cGMP Pathway in Cancer. Sex. Med. Rev. 2016, 4, 74–84.
    36. Mao, Y.; Sarhan, D.; Steven, A.; Seliger, B.; Kiessling, R.; Lundqvist, A. Inhibition of tumor-derived prostaglandin-e2 blocks the induction of myeloid-derived suppressor cells and recovers natural killer cell activity. Clin. Cancer Res. 2014, 20, 4096–4106.
    37. Butowski, N.; Colman, H.; De Groot, J.F.; Omuro, A.M.; Nayak, L.; Wen, P.Y.; Cloughesy, T.F.; Marimuthu, A.; Haidar, S.; Perry, A.; et al. Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: An Ivy Foundation Early Phase Clinical Trials Consortium phase II study. Neuro. Oncol. 2016, 18, 557–564.
    38. Flores-Toro, J.A.; Luo, D.; Gopinath, A.; Sarkisian, M.R.; Campbell, J.J.; Charo, I.F.; Singh, R.; Schall, T.J.; Datta, M.; Jain, R.K.; et al. CCR2 inhibition reduces tumor myeloid cells and unmasks a checkpoint inhibitor effect to slow progression of resistant murine gliomas. Proc. Natl. Acad. Sci. USA 2020, 117, 1129–1138.
    39. Nefedova, Y.; Fishman, M.; Sherman, S.; Wang, X.; Beg, A.A.; Gabrilovich, D.I. Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res. 2007, 67, 11021–11028.
    40. Wang, R.; Liu, C. All-trans retinoic acid therapy induces asymmetric division of glioma stem cells from the U87MG cell line. Oncol. Lett. 2019, 18, 3646–3654.
    41. Chang, Q.; Chen, Z.; You, J.; McNutt, M.A.; Zhang, T.; Han, Z.; Zhang, X.; Gong, E.; Gu, J. All-trans-retinoic acid induces cell growth arrest in a human medulloblastoma cell line. J. Neurooncol. 2007, 84, 263–267.
    42. Gumireddy, K.; Sutton, L.N.; Phillips, P.C.; Reddy, C.D. All-trans-retinoic acid-induced apoptosis in human medulloblastoma: Activation of caspase-3/poly(ADP-ribose) polymerase 1 pathway. Clin. Cancer Res. 2003, 9, 4052–4059.
    43. Schmoch, T.; Gal, Z.; Mock, A.; Mossemann, J.; Lahrmann, B.; Grabe, N.; Schmezer, P.; Lasitschka, F.; Beckhove, P.; Unterberg, A.; et al. Combined Treatment of ATRA with Epigenetic Drugs Increases Aggressiveness of Glioma Xenografts. Anticancer Res. 2016, 36, 1489–1496.
    More