Journal of Neuro-Oncology

, Volume 123, Issue 3, pp 405–412 | Cite as

The role of regulatory T cells and microglia in glioblastoma-associated immunosuppression

  • Alfred P. See
  • Jonathon J. Parker
  • Allen Waziri
Editors' Invited Manuscript


Cell-mediated suppression of anti-tumor immunity is multifactorial in patients with cancer, and recent studies have focused on several distinct cellular agents that are associated with this phenomenon. This review will focus on the potential role of regulatory T cells (Tregs) and microglia in the suppression of cellular immunity observed in patients with glioblastoma. We discuss the ontogeny, basic biology, evidence for activity, and potential clinical options for targeting Tregs and microglia as part of immunotherapy in affected patients.


Glioblastoma Treg Microglia MDSC Immunosuppression 


  1. 1.
    Beyer M, Schultze JL (2006) Regulatory T cells in cancer. Blood 108:804–811PubMedCrossRefGoogle Scholar
  2. 2.
    Paust S, Lu L, McCarty N, Cantor H (2004) Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease. Proc Natl Acad Sci USA 101:10398–10403PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Whiteside T (2012) What are regulatory T cells (Treg) regulating in cancer and why? Semin Cancer Biol 22:327–334PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Ebert LM, Tan BS, Browning J et al (2008) The regulatory T cell-associated transcription factor FoxP3 is expressed by tumor cells. Cancer Res 68:3001–3009PubMedCrossRefGoogle Scholar
  5. 5.
    Fontenot JD, Gavin MA, Rudensky AY. (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336.CrossRefGoogle Scholar
  6. 6.
    Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061PubMedCrossRefGoogle Scholar
  7. 7.
    Read S, Malmstrom V, Powrie F (2000) Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 192:295–302PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Takahashi T, Tagami T, Yamazaki S et al (2000) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192:303–310PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Whiteside TL, Schuler P, Schilling B (2012) Induced and natural regulatory T cells in human cancer. Expert Opin Biol Ther 12:1383–1397PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    von Boehmer H (2005) Mechanisms of suppression by suppressor T cells. Nat Immunol 6:338–344CrossRefGoogle Scholar
  11. 11.
    Grossman WJ, Verbsky JW, Barchet W et al (2004) Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21:589–601PubMedCrossRefGoogle Scholar
  12. 12.
    Wainwright DA, Balyasnikova IV, Chang AL et al (2012) IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin Cancer Res 18:6110–6121PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Hara M, Kingsley CI, Niimi M et al (2001) IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J Immunol 166:3789–3796PubMedCrossRefGoogle Scholar
  14. 14.
    Nakamura K, Kitani A, Strober W (2001) Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 194:629–644PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Elkord E, Sharma S, Burt DJ, Hawkins RE (2011) Expanded subpopulation of FoxP3+ T regulatory cells in renal cell carcinoma co-express helios, indicating they could be derived from natural but not induced Tregs. Clin Immunol 140:218–222PubMedCrossRefGoogle Scholar
  16. 16.
    Wainwright DA, Sengupta S, Han Y, Lesniak MS (2011) Thymus-derived rather than tumor-induced regulatory T cells predominate in brain tumors. Neuro Oncol 13:1308–1323PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Alizadeh D, Katsanis E, Larmonier N (2013) The multifaceted role of Th17 lymphocytes and their associated cytokines in cancer. Clin Dev Immunol 2013:1–11CrossRefGoogle Scholar
  18. 18.
    Duan MC, Zhong XN, Liu GN, Wei JR (2014) The Treg/Th17 paradigm in lung cancer. J Immunol Res 2014:1−9Google Scholar
  19. 19.
    Koenen HJ, Smeets RL, Vink PM, van Rijssen E, Boots AM, Joosten I (2008) Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 112(6):2340–2352Google Scholar
  20. 20.
    Zhou L, Lopes JE, Chong MM et al (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453:236–240PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Yang XO, Nurieva R, Martinez GJ et al (2008) Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29:44–56PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Fecci PE, Mitchell DA, Whitesides JF et al (2006) Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res 66:3294–3302PubMedCrossRefGoogle Scholar
  23. 23.
    El Andaloussi A, Lesniak MS (2006) An increase in CD4+CD25+FOXP3+ regulatory T cells in tumor-infiltrating lymphocytes of human glioblastoma multiforme. Neuro Oncol 8:234–243PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Waziri A, Killory B, Ogden AT et al (2008) Preferential in situ CD4+CD56+ T cell activation and expansion within human glioblastoma. J Immunol 180:7673–7680PubMedCrossRefGoogle Scholar
  25. 25.
    Lohr J, Ratliff T, Huppertz A et al (2011) Effector T-cell infiltration positively impacts survival of glioblastoma patients and is impaired by tumor-derived TGF-β. Clin Cancer Res 17:4296–4308PubMedCrossRefGoogle Scholar
  26. 26.
    Heimberger AB, Abou-Ghazal M, Reina-Ortiz C et al (2008) Incidence and prognostic impact of FoxP3+ regulatory T cells in human gliomas. Clin Cancer Res 14:5166–5172PubMedCrossRefGoogle Scholar
  27. 27.
    El Andaloussi A, Lesniak MS (2007) CD4+CD25+FoxP3+ T-cell infiltration and heme oxygenase-1 expression correlate with tumor grade in human gliomas. J Neurononcol 83:145–152CrossRefGoogle Scholar
  28. 28.
    Jacobs JF, Idema AJ, Bok KF et al (2010) Prognostic significance and mechanisms of Treg infiltration in human brain tumors. J Neuroimmunol 225:195–199PubMedCrossRefGoogle Scholar
  29. 29.
    Fadul CE, Fisher JL, Gui J et al (2011) Immune modulation effects of concomitant temozolomide and radiation therapy on peripheral blood mononuclear cells in patients with glioblastoma multiforme. Neuro Oncol 13:393–400PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Sampson JH, Aldape KD, Archer GE et al (2011) Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol 13:324–333PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Zeng J, See AP, Phallen J et al (2013) Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys 86:343–349PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Curtin JF, Candolfi M, Fakhouri TM et al (2008) Treg depletion inhibits efficacy of cancer immunotherapy: implications for clinical trials. PLoS One 3:e1983PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Rech AJ, Mick R, Martin S, et al. (2012) CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci Transl Med 4:134ra62.Google Scholar
  34. 34.
    Jacobs JF, Punt CJ, Lesterhuis WJ et al (2010) Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients. Clin Cancer Res 16:5067–5078PubMedCrossRefGoogle Scholar
  35. 35.
    Sampson JH, Schmittling RJ, Archer GE et al (2012) A pilot study of IL-2Ra blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma. PLoS One 7:e31046PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Turturro F (2007) Denileukin diftitox: a biotherapeutic paradigm shift in the treatment of lymphoid-derived disorders. Expert Rev Anticancer Ther 7:11–17PubMedCrossRefGoogle Scholar
  37. 37.
    Wainwright DA, Chang AL, Dey M et al (2014) Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin Cancer Res 20:5290–5301Google Scholar
  38. 38.
    Bronte V (2009) Myeloid-derived suppressor cells in inflammation: uncovering cell subsets with enhanced immunosuppressive functions. Eur J Immunol 39:2670–2672PubMedCrossRefGoogle Scholar
  39. 39.
    Almand B, Clark JI, Nikitina E et al (2001) Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 166:678–689PubMedCrossRefGoogle Scholar
  40. 40.
    Kusmartsev S, Su Z, Heiser A et al (2008) Reversal of myeloid cell-mediated immunosuppression in patients with metastatic renal cell carcinoma. Clin Cancer Res 14:8270–8278PubMedCrossRefGoogle Scholar
  41. 41.
    Poschke I, Mougiakakos D, Hansson J, Masucci GV, Kiessling R (2010) Immature immunosuppressive CD14+HLA-DR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign. Cancer Res 70:4335–4345PubMedCrossRefGoogle Scholar
  42. 42.
    Mirza N, Fishman M, Fricke I et al (2006) All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res 66:9299–9307PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Galdiero MR, Bonavita E, Barajon I et al (2013) Tumor associated macrophages and neutrophils in cancer. Immunobiology 218:1402–1410PubMedCrossRefGoogle Scholar
  44. 44.
    Peranzoni E, Zilio S, Marigo I et al (2010) Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol 22:238–244PubMedCrossRefGoogle Scholar
  45. 45.
    Sippel TR, White J, Nag K et al (2011) Neutrophil degranulation and immunosuppression in patients with GBM: restoration of cellular immune function by targeting arginase I. Clin Cancer Res 17:6992–7002PubMedCrossRefGoogle Scholar
  46. 46.
    Gustafson MP, Lin Y, New KC et al (2010) Systemic immune suppression in glioblastoma: the interplay between CD14+HLA-DRlo/neg monocytes, tumor factors, and dexamethasone. Neuro Oncol 12:631–644PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Raychaudhuri B, Rayman P, Ireland J et al (2011) Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma. Neuro Oncol 13:591–599PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    da Fonseca AC, Badie B (2013) Microglia and macrophages in malignant gliomas: recent discoveries and implications for promising therapies. Clin Dev Immunol 2013:264124PubMedGoogle Scholar
  49. 49.
    Mantovani A, Sozzani S, Locati M et al (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549–555PubMedCrossRefGoogle Scholar
  50. 50.
    Wang N, Liang H, Zen K (2014) Molecular mechanisms that influence the macrophage m1–m2 polarization balance. Front Immunol 5:614PubMedCentralPubMedGoogle Scholar
  51. 51.
    Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318Google Scholar
  52. 52.
    Davalos D, Grutzendler J, Yang G et al (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758PubMedCrossRefGoogle Scholar
  53. 53.
    Dailey ME, Waite M (1999) Confocal imaging of microglial cell dynamics in hippocampal slice cultures. Methods 18:222–30Google Scholar
  54. 54.
    Kurpius D, Nolley EP, Dailey ME (2007) Purines induce directed migration and rapid homing of microglia to injured pyramidal neurons in developing hippocampus. Glia 5:873–884Google Scholar
  55. 55.
    Ginhoux F, Lim S, Hoeffel G, Low D, Huber T (2013) Origin and differentiation of microglia. Front Cell Neurosci 7:45PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Aloisi F, De Simone R, Columba-Cabezas S, Penna G, Adorini LB (2000) Functional maturation of adult mouse resting microglia into an APC is promoted by granulocyte-macrophage colony-stimulating factor and interaction with Th1 cells. J Immunol 164:1705–1712Google Scholar
  57. 57.
    Lynch MA (2009) The multifaceted profile of activated microglia. Mol Neurobiol 40:139–156PubMedCrossRefGoogle Scholar
  58. 58.
    Graeber MB, Scheithauer BW, Kreutzberg GW (2002) Microglia in brain tumors. Glia 40:252–259Google Scholar
  59. 59.
    Parker JJ, Dionne KR, Massarwa R et al (2013) Gefitinib selectively inhibits tumor cell migration in EGFR-amplified human glioblastoma. Neuro Oncol 15:1048–1057PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Facoetti A, Nano R, Zelini P et al (2005) Human leukocyte antigen and antigen processing machinery component defects in astrocytic tumors. Clin Cancer Res 11:8304–8311PubMedCrossRefGoogle Scholar
  61. 61.
    Kostianovsky AM, Maier LM, Anderson RC, Bruce JN, Anderson DE (2008) Astrocytic regulation of human monocytic/microglial activation. J Immunol 181:5425–5432PubMedCrossRefGoogle Scholar
  62. 62.
    Badie B, Schartner J, Prabakaran S, Paul J, Vorpahl JB (2001) Expression of Fas ligand by microglia: possible role in glioma immune evasion. J Neuroimmunol 120:19–24Google Scholar
  63. 63.
    Rodrigues JC, Gonzalez GC, Zhang L et al (2010) Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro Oncol 12:351–365PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Kortylewski M, Yu H (2008) Role of Stat3 in suppressing anti-tumor immunity. Curr Opin Immunol 20:228–233PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Abou-Ghazal M, Yang DS, Qiao W et al (2008) The incidence, correlation with tumor-infiltrating inflammation, and prognosis of phosphorylated STAT3 expression in human gliomas. Clin Cancer Res 14:8228–8235PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Wu A, Wei J, Kong LY et al (2010) Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro Oncol 12:1113–1125PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Zhang L, Alizadeh D, Van Handel M et al (2009) Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice. Glia 57:1458–1467PubMedCrossRefGoogle Scholar
  68. 68.
    Wei J, Barr J, Kong LY et al (2010) Glioblastoma cancer-initiating cells inhibit T-cell proliferation and effector responses by the signal transducers and activators of transcription 3 pathway. Mol Cancer Ther 9:67–78PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Wei J, Wang F, Kong LY et al (2013) miR-124 inhibits STAT3 signaling to enhance T cell-mediated immune clearance of glioma. Cancer Res 73:3913–3926PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Zhao D, Alizadeh D, Zhang L et al (2011) Carbon nanotubes enhance CpG uptake and potentiate antiglioma immunity. Clin Cancer Res 17:771–782PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Allavena P, Mantovani A (2012) Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin Exp Immunol 167:195–205Google Scholar
  72. 72.
    Cunningham CL, Martínez-Cerdeño V, Noctor SC (2013) Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci. 33:4216–4233PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Alfred P. See
    • 1
  • Jonathon J. Parker
    • 2
  • Allen Waziri
    • 3
  1. 1.Department of Neurological SurgeryBrigham and Women’s HospitalBostonUSA
  2. 2.University of Colorado School of MedicineDenverUSA
  3. 3.Department of NeurosurgeryInova Neuroscience InstituteFalls ChurchUSA

Personalised recommendations