Skip to main content

Advertisement

SpringerLink
Log in

Generation and immunologic functions of Th17 cells in malignant gliomas

  • Original article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Th17 cells, a recently discovered inflammatory T cell subtype, have been implicated with autoimmune disorders. However, mechanism of generation or functions of intratumoral Th17 cells are still unclear. We have been investigating the mechanism of induction and role of Th17 cells in malignant gliomas using primary tumor as well as cell lines. We report here that: (1) a higher frequency of Th17 cells in gliomas were associated with higher number of myeloid (CD11b) cells as well as the expression of TGF-β1 or IL-6; (2) conditioned medium from glioma cells (Gl CM) induced Th17 cell differentiation, which was inhibited by anti-TGF-β1 and anti-IL-6; (3) glioma-associated monocytes secreted Th17-promoting cytokines IL-1β and IL-23; (4) CM from glioma and monocyte co-culture (Gl+Mo CM) induced high frequency of Th17 cells in naïve T cell culture, which was abrogated by anti-IL-1β and anti-IL-23 antibodies; (5) In vitro Gl+Mo CM-mediated Th17 generation was associated with a decrease in IFN-γ and a concomitant increase in IL-10 secretion. Anti-TGF-β1, but not anti-IL-6, significantly reversed this cytokine profile. These results demonstrate prevalence of Th17 cells in gliomas and implicate the cytokines derived from the tumor as well as infiltrating myeloid cells in the induction of Th17 cells in glioma microenvironment. Moreover, the data also suggest that glioma-associated Th17 cells may contribute to immune-suppression via TGF-β1-induced IL-10 secretion. Further studies on the mechanism of tumor-infiltration, developmental pathways, and pro-/anti-tumor functions of Th17 cells will provide rationale for developing novel adjuvant immunotherapeutic strategies for malignant gliomas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

CM:

Conditioned medium

nT:

Naïve T cells

GI-CM:

Conditioned medium from glioma cells

Mo-CM:

Conditioned medium from monocyte culture

TGF:

Transforming growth factor

CCL:

Chemokine ligand

References

  1. CBTRUS: CBTRUS Statistical report: primary brain and central nervous system tumors diagnosed in the United States, 2004–2006. Central Brain Tumor Registry of the United States, 2010

  2. Cancer facts and figures. American Cancer Society, 2010

  3. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466

    Article  PubMed  CAS  Google Scholar 

  4. Cole SW (2009) Chronic inflammation and breast cancer recurrence. J Clin Oncol 27:3418–3419

    Article  PubMed  Google Scholar 

  5. Aggarwal BB, Gehlot P (2009) Inflammation and cancer: how friendly is the relationship for cancer patients? Curr Opin Pharmacol 9:351–369

    Article  PubMed  CAS  Google Scholar 

  6. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238

    Article  PubMed  CAS  Google Scholar 

  7. Zou W, Restifo NP (2010) T(H)17 cells in tumour immunity and immunotherapy. Nat Rev Immunol 10:248–256

    Article  PubMed  CAS  Google Scholar 

  8. Bronte V (2008) Th17 and cancer: friends or foes? Blood 112:214

    Article  PubMed  CAS  Google Scholar 

  9. Zhu J, Paul WE (2010) Peripheral CD4 + T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev 238:247–262

    Article  PubMed  CAS  Google Scholar 

  10. Schneider J, Hofman FM, Apuzzo ML, Hinton DR (1992) Cytokines and immunoregulatory molecules in malignant glial neoplasms. J Neurosurg 77:265–273

    Article  PubMed  CAS  Google Scholar 

  11. Parajuli P, Mathupala S, Mittal S, Sloan AE (2007) Dendritic cell-based active specific immunotherapy for malignant glioma. Expert Opin Biol Ther 7:439–448

    Article  PubMed  CAS  Google Scholar 

  12. Zou JP, Morford LA, Chougnet C, Dix AR, Brooks AG, Torres N, Shuman JD, Coligan JE, Brooks WH, Roszman TL, Shearer GM (1999) Human glioma-induced immunosuppression involves soluble factor(s) that alters monocyte cytokine profile and surface markers. J Immunol 162:4882–4892

    PubMed  CAS  Google Scholar 

  13. Gomez GG, Kruse CA (2007) Cellular and functional characterization of immunoresistant human glioma cell clones selected with alloreactive cytotoxic T lymphocytes reveals their up-regulated synthesis of biologically active TGF-beta. J Immunother 30:261–273

    Article  PubMed  CAS  Google Scholar 

  14. Morishima N, Mizoguchi I, Takeda K, Mizuguchi J, Yoshimoto T (2009) TGF-beta is necessary for induction of IL-23R and Th17 differentiation by IL-6 and IL-23. Biochem Biophys Res Commun 386:105–110

    Article  PubMed  CAS  Google Scholar 

  15. Zhu J, Paul WE (2010) Heterogeneity and plasticity of T helper cells. Cell Res 20:4–12

    Article  PubMed  Google Scholar 

  16. Hussain SF, Yang D, Suki D, Aldape K, Grimm E, Heimberger AB (2006) The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro Oncol 8:261–279

    Article  PubMed  CAS  Google Scholar 

  17. Leung SY, Wong MP, Chung LP, Chan AS, Yuen ST (1997) Monocyte chemoattractant protein-1 expression and macrophage infiltration in gliomas. Acta Neuropathol 93:518–527

    Article  PubMed  CAS  Google Scholar 

  18. Takeshima H, Kuratsu J, Takeya M, Yoshimura T, Ushio Y (1994) Expression and localization of messenger RNA and protein for monocyte chemoattractant protein-1 in human malignant glioma. J Neurosurg 80:1056–1062

    Article  PubMed  CAS  Google Scholar 

  19. Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL (2003) Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 278:1910–1914

    Article  PubMed  CAS  Google Scholar 

  20. Yu RY, Gallagher G (2010) A naturally occurring, soluble antagonist of human IL-23 inhibits the development and in vitro function of human Th17 cells. J Immunol 185:7302–7308

    Article  PubMed  CAS  Google Scholar 

  21. Aliahmadi E, Gramlich R, Grutzkau A, Hitzler M, Kruger M, Baumgrass R, Schreiner M, Wittig B, Wanner R, Peiser M (2009) TLR2-activated human langerhans cells promote Th17 polarization via IL-1beta, TGF-beta and IL-23. Eur J Immunol 39:1221–1230

    Article  PubMed  CAS  Google Scholar 

  22. Sha Y, Markovic-Plese S (2011) A role of IL-1R1 signaling in the differentiation of Th17 cells and the development of autoimmune diseases. Self Nonself 2:35–42

    PubMed  Google Scholar 

  23. Kuang DM, Peng C, Zhao Q, Wu Y, Chen MS, Zheng L (2010) Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology 51:154–164

    Article  PubMed  CAS  Google Scholar 

  24. Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, Huang E, Finlayson E, Simeone D, Welling TH, Chang A, Coukos G, Liu R, Zou W (2009) Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 114:1141–1149

    Article  PubMed  CAS  Google Scholar 

  25. Sloan AE, Parajuli P (2003) Human autologous dendritic cell-glioma fusions: feasibility and capacity to stimulate T cells with proliferative and cytolytic activity. J Neurooncol 64:177–183

    PubMed  Google Scholar 

  26. Parajuli P, Mathupala S, Sloan AE (2004) Systematic comparison of dendritic cell-based immunotherapeutic strategies for malignant gliomas: in vitro induction of cytolytic and natural killer-like T cells. Neurosurgery 55:1194–1204

    Article  PubMed  Google Scholar 

  27. Bergmann C, Strauss L, Zeidler R, Lang S, Whiteside TL (2007) Expansion of human T regulatory type 1 cells in the microenvironment of cyclooxygenase 2 overexpressing head and neck squamous cell carcinoma. Cancer Res 67:8865–8873

    Article  PubMed  CAS  Google Scholar 

  28. Fantini MC, Dominitzki S, Rizzo A, Neurath MF, Becker C (2007) In vitro generation of CD4 + CD25 + regulatory cells from murine naive T cells. Nat Protoc 2:1789–1794

    Article  PubMed  CAS  Google Scholar 

  29. Parajuli P, Joshee N, Chinni SR, Rimando AM, Mittal S, Sethi S, Yadav AK (2011) Delayed growth of glioma by Scutellaria flavonoids involve inhibition of Akt, GSK-3 and NF-kappaB signaling. J Neurooncol 101:15–24

    Article  PubMed  Google Scholar 

  30. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22(4):719–748

    PubMed  CAS  Google Scholar 

  31. Scheck AC, Perry K, Hank NC, Clark WD (2006) Anticancer activity of extracts derived from the mature roots of Scutellaria baicalensis on human malignant brain tumor cells. BMC Complement Altern Med 6:27

    Article  PubMed  Google Scholar 

  32. Folkins C, Shaked Y, Man S, Tang T, Lee CR, Zhu Z, Hoffman RM, Kerbel RS (2009) Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1. Cancer Res 69:7243–7251

    Article  PubMed  CAS  Google Scholar 

  33. Kerber M, Reiss Y, Wickersheim A, Jugold M, Kiessling F, Heil M, Tchaikovski V, Waltenberger J, Shibuya M, Plate KH, Machein MR (2008) Flt-1 signaling in macrophages promotes glioma growth in vivo. Cancer Res 68:7342–7351

    Article  PubMed  CAS  Google Scholar 

  34. Derhovanessian E, Adams V, Hahnel K, Groeger A, Pandha H, Ward S, Pawelec G (2009) Pretreatment frequency of circulating IL-17 + CD4 + T-cells, but not Tregs, correlates with clinical response to whole-cell vaccination in prostate cancer patients. Int J Cancer 125:1372–1379

    Article  PubMed  CAS  Google Scholar 

  35. Hong X, Jiang F, Kalkanis SN, Zhang ZG, Zhang X, Zheng X, Jiang H, Mikkelsen T, Chopp M (2008) Increased chemotactic migration and growth in heparanase-overexpressing human U251n glioma cells. J Exp Clin Cancer Res 27:23

    Article  PubMed  Google Scholar 

  36. Wainwright DA, Sengupta S, Han Y, Ulasov IV, Lesniak MS (2010) The presence of IL-17A and T helper 17 cells in experimental mouse brain tumors and human glioma. PLoS One 5:e15390

    Article  PubMed  Google Scholar 

  37. Maniati E, Soper R, Hagemann T (2010) Up for Mischief? IL-17/Th17 in the tumour microenvironment. Oncogene 29:5653–5662

    Article  PubMed  CAS  Google Scholar 

  38. Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O’Shea JJ (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467:967–971

    Article  PubMed  CAS  Google Scholar 

  39. Benwell RK, Lee DR (2010) Essential and synergistic roles of IL1 and IL6 in human Th17 differentiation directed by TLR ligand-activated dendritic cells. Clin Immunol 134:178–187

    Article  PubMed  CAS  Google Scholar 

  40. Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, Kang HS, Ma L, Watowich SS, Jetten AM, Tian Q, Dong C (2009) Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30:576–587

    Article  PubMed  CAS  Google Scholar 

  41. Dong C (2008) TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 8:337–348

    Article  PubMed  CAS  Google Scholar 

  42. Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O’Shea JJ (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467:967–971

    Google Scholar 

  43. Kuang DM, Peng C, Zhao Q, Wu Y, Zhu LY, Wang J, Yin XY, Li L, Zheng L (2010) Tumor-activated monocytes promote expansion of IL-17-producing CD8 + T cells in hepatocellular carcinoma patients. J Immunol 185:1544–1549

    Article  PubMed  CAS  Google Scholar 

  44. Domingues HS, Mues M, Lassmann H, Wekerle H, Krishnamoorthy G (2010) Functional and pathogenic differences of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. PLoS One 5:e15531

    Article  PubMed  CAS  Google Scholar 

  45. Annunziato F, Romagnani S (2010) The transient nature of the Th17 phenotype. Eur J Immunol 40:3312–3316

    Article  PubMed  CAS  Google Scholar 

  46. Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR, Huso DL, Brancati FL, Wick E, McAllister F, Housseau F, Pardoll DM, Sears CL (2009) A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 15:1016–1022

    Article  PubMed  CAS  Google Scholar 

  47. Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H (2009) IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med 206:1457–1464

    Article  PubMed  CAS  Google Scholar 

  48. Li J, Huang ZF, Xiong G, Mo HY, Qiu F, Mai HQ, Chen QY, He J, Chen SP, Zheng LM, Qian CN, Zeng YX (2011) Distribution, characterization, and induction of CD8 + regulatory T cells and IL-17-producing CD8 + T cells in nasopharyngeal carcinoma. J Transl Med 9:189

    Article  PubMed  CAS  Google Scholar 

  49. Garcia-Hernandez Mde L, Hamada H, Reome JB, Misra SK, Tighe MP, Dutton RW (2010) Adoptive transfer of tumor-specific Tc17 effector T cells controls the growth of B16 melanoma in mice. J Immunol 184:4215–4227

    Article  PubMed  Google Scholar 

  50. Tajima M, Wakita D, Satoh T, Kitamura H, Nishimura T (2011) IL-17/IFN-gamma double producing CD8 + T (Tc17/IFN-gamma) cells: a novel cytotoxic T-cell subset converted from Tc17 cells by IL-12. Int Immunol 23:751–759

    Article  PubMed  CAS  Google Scholar 

  51. Numasaki M, Fukushi J, Ono M, Narula SK, Zavodny PJ, Kudo T, Robbins PD, Tahara H, Lotze MT (2003) Interleukin-17 promotes angiogenesis and tumor growth. Blood 101:2620–2627

    Article  PubMed  CAS  Google Scholar 

  52. Benchetrit F, Ciree A, Vives V, Warnier G, Gey A, Sautes-Fridman C, Fossiez F, Haicheur N, Fridman WH, Tartour E (2002) Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood 99:2114–2121

    Article  PubMed  CAS  Google Scholar 

  53. Hirahara N, Nio Y, Sasaki S, Minari Y, Takamura M, Iguchi C, Dong M, Yamasawa K, Tamura K (2001) Inoculation of human interleukin-17 gene-transfected Meth-A fibrosarcoma cells induces T cell-dependent tumor-specific immunity in mice. Oncology 61:79–89

    Article  PubMed  CAS  Google Scholar 

  54. Zhou L, Chong MM, Littman DR (2009) Plasticity of CD4 + T cell lineage differentiation. Immunity 30:646–655

    Article  PubMed  CAS  Google Scholar 

  55. Nistala K, Adams S, Cambrook H, Ursu S, Olivito B, de Jager W, Evans JG, Cimaz R, Bajaj-Elliott M, Wedderburn LR (2010) Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci USA 107:14751–14756

    Article  PubMed  CAS  Google Scholar 

  56. Volpe E, Touzot M, Servant N, Marloie-Provost MA, Hupe P, Barillot E, Soumelis V (2009) Multiparametric analysis of cytokine-driven human Th17 differentiation reveals a differential regulation of IL-17 and IL-22 production. Blood 114:3610–3614

    Article  PubMed  CAS  Google Scholar 

  57. Zhao F, Hoechst B, Gamrekelashvili J, Ormandy LA, Voigtlander T, Wedemeyer H, Ylaya K, Wang XW, Hewitt SM, Manns MP, Korangy F, Greten TF (2012) Human CCR4 + CCR6 + Th17 cells suppress autologous CD8 + T cell responses. J Immunol 188:6055–6062

    Article  PubMed  CAS  Google Scholar 

  58. Johnson LA, Sampson JH (2010) Immunotherapy approaches for malignant glioma from 2007 to 2009. Curr Neurol Neurosci Rep 10:259–266

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We acknowledge research support from the Fund for Medical Research and Education (FMRE) to PP. The Microscopy, Imaging and Cytometry Resources Core is supported, in part, by NIH Center grant P30CA22453 to The Karmanos Cancer Institute, Wayne State University and the Perinatology Research Branch of the National Institutes of Child Health and Development, Wayne State University. We are thankful to Dr. Indrajit Sinha for his critical evaluation of the manuscript and also for his help with the preparation of the Figures.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Karmanos Cancer Institute, Wayne State University, 550 E. Canfield, Lande Bldg #460, Detroit, MI, 48201, USA

    Manjeera Paladugu, Sandeep Mittal & Prahlad Parajuli

  2. Department of Oncology, Medicine and Immunology and Microbiology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    Archana Thakur & Lawrence G. Lum

Authors
  1. Manjeera Paladugu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Archana Thakur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lawrence G. Lum
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sandeep Mittal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Prahlad Parajuli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Prahlad Parajuli.

Electronic supplementary material

Below is the link to the electronic supplementary material.

262_2012_1312_MOESM1_ESM.ppt

Supplementary Figure S1. Prevalence of Th17 cells in gliomas. Paraffinized tumor sections, obtained from patients with malignant glioma were analyzed by IHC to determine the presence of CD4+IL-17+ Th17 cells (A); Isotype antibody control staining were also performed to rule out the background (B). The micrographs were imaged at 200x magnification (PPT 1389 kb)

262_2012_1312_MOESM2_ESM.ppt

Supplementary Figure S2. Isotype Controls for data presented in Figure 6. nT cells were cultured, stained with isotype control antibodies and were analyzed by flow cytometry, as described under Figure 6. The data are from one representative experiment out of three experiments performed with similar results (PPT 294 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Paladugu, M., Thakur, A., Lum, L.G. et al. Generation and immunologic functions of Th17 cells in malignant gliomas. Cancer Immunol Immunother 62, 75–86 (2013). https://doi.org/10.1007/s00262-012-1312-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-012-1312-7

Keywords

Search

Navigation