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A critical role for regulatory T cells in driving cytokine profiles of Th17 cells and their modulation of glioma microenvironment

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Abstract

IL-17A, produced by Th17 cells, may play a dual role in antitumor immunity. Using the GL261-glioma model, we investigated the effects of Th17 cells on tumor growth and microenvironment. Th17 cells infiltrate mouse gliomas, increase significantly in a time-dependent manner similarly to Treg and do not express Foxp3. To characterize the direct effects of Th17 cells on GL261 murine gliomas and on tumor microenvironment, we isolated IL-17-producing cells enriched from splenocytes derived from naïve (nTh17) or glioma-bearing mice (gTh17) and pre-stimulated in vitro with or without TGF-β. Spleen-derived Th17 cells co-expressing IL-17, IFN-γ and IL-10, but not Treg marker Foxp3, were co-injected intracranially with GL261 in immune-competent mice. Mice co-injected with GL261 and nTh17 survived significantly longer than gTh17 (P < 0.006) and gliomas expressed high level of IFN-γ and TNF-α, low levels of IL-10 and TGF-β. In vitro IL-17 per se did not exert effects on GL261 proliferation; in vivo gliomas grew equally well intracranially in IL-17 deficient and wild-type mice. We further analyzed relationship between Th17 cells and Treg. Treg were significantly higher in splenocytes from glioma-bearing than naïve mice (P = 0.01) and gTh17 produced more IL-10 than IFN-γ (P = 0.002). In vitro depletion of Treg using PC61 in splenocytes from glioma-bearing mice causes increased IL-17/IFN-γ cells (P = 0.007) and decreased IL-17/IL-10 cells (P = 0.03). These results suggest that Th17 polarization may be induced by Treg and that Th17 cells in gliomas modulate tumor growth depending on locally produced cytokines.

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References

  1. Steinman L (2007) A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med 13:139–145

    Article  PubMed  CAS  Google Scholar 

  2. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123–1132

    Article  PubMed  CAS  Google Scholar 

  3. Stockinger B, Veldhoen M (2007) Differentiation and function of Th17 T cells. Curr Opin Immunol 19:281–286

    Article  PubMed  CAS  Google Scholar 

  4. Das J, Ren G, Zhang L, Roberts AI, Zhao X, Bothwell AL, Van Kaer L, Shi Y, Das G (2009) Transforming growth factor beta is dispensable for the molecular orchestration of Th17 cell differentiation. J Exp Med 206:2407–2416

    Article  PubMed  CAS  Google Scholar 

  5. Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, Blank RB, Meylan F, Siegel R, Hennighausen L, Shevach EM, O’shea JJ (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26:371–381

    Article  PubMed  CAS  Google Scholar 

  6. McGeachy MJ, Cua DJ (2008) Th17 cell differentiation: the long and winding road. Immunity 28:445–453

    Article  PubMed  CAS  Google Scholar 

  7. Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, Basham B, Smith K, Chen T, Morel F, Lecron JC, Kastelein RA, Cua DJ, McClanahan TK, Bowman EP, de Waal Malefyt R (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 8:950–957

    Article  PubMed  CAS  Google Scholar 

  8. Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C (2008) T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28:29–39

    Article  PubMed  CAS  Google Scholar 

  9. Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupe P, Barillot E, Soumelis V (2008) A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol 9:650–657

    Article  PubMed  CAS  Google Scholar 

  10. Manel N, Unutmaz D, Littman DR (2008) The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 9:641–649

    Article  PubMed  CAS  Google Scholar 

  11. Miyahara Y, Odunsi K, Chen W, Peng G, Matsuzaki J, Wang RF (2008) Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer. Proc Natl Acad Sci USA 105:15505–15510

    Article  PubMed  CAS  Google Scholar 

  12. 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 

  13. Sfanos KS, Bruno TC, Maris CH, Xu L, Thoburn CJ, DeMarzo AM, Meeker AK, Isaacs WB, Drake CG (2008) Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res 14:3254–3261

    Article  PubMed  CAS  Google Scholar 

  14. Zhang B, Rong G, Wei H, Zhang M, Bi J, Ma L, Xue X, Wei G, Liu X, Fang G (2008) The prevalence of Th17 cells in patients with gastric cancer. Biochem Biophys Res Commun 374:533–537

    Article  PubMed  CAS  Google Scholar 

  15. Su X, Ye J, Hsueh EC, Zhang Y, Hoft DF, Peng G (2010) Tumor microenvironments direct the recruitment and expansion of human Th17 cells. J Immunol 184:1630–1641

    Article  PubMed  CAS  Google Scholar 

  16. Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, Hwu P, Restifo NP, Overwijk WW, Dong C (2009) T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity 31:787–798

    Article  PubMed  CAS  Google Scholar 

  17. Muranski P, Boni A, Antony PA, Cassard L, Irvine KR, Kaiser A, Paulos CM, Palmer DC, Touloukian CE, Ptak K, Gattinoni L, Wrzesinski C, Hinrichs CS, Kerstann KW, Feigenbaum L, Chan CC, Restifo NP (2008) Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 112:362–373

    Article  PubMed  CAS  Google Scholar 

  18. 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 

  19. Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4+ CD25+ T cell-mediated suppression by dendritic cells. Science 299:1033–1036

    Article  PubMed  CAS  Google Scholar 

  20. Gounaris E, Blatner NR, Dennis K, Magnusson F, Gurish MF, Strom TB, Beckhove P, Gounari F, Khazaie K (2009) T-regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposis. Cancer Res 69:5490–5497

    Article  PubMed  CAS  Google Scholar 

  21. Viaud S, Flament C, Zoubir M, Pautier P, LeCesne A, Ribrag V, Soria JC, Marty V, Vielh P, Robert C, Chaput N, Zitvogel L (2011) Cyclophosphamide induces differentiation of Th17 cells in cancer patients. Cancer Res 71:661–665

    Article  PubMed  CAS  Google Scholar 

  22. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189

    Article  PubMed  CAS  Google Scholar 

  23. 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 

  24. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F (2007) Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8:942–949

    Article  PubMed  CAS  Google Scholar 

  25. Kryczek I, Wei S, Zou L, Altuwaijri S, Szeliga W, Kolls J, Chang A, Zou W (2007) Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol 178:6730–6733

    PubMed  CAS  Google Scholar 

  26. Pellegatta S, Poliani PL, Stucchi E, Corno D, Colombo CA, Orzan F, Ravanini M, Finocchiaro G (2010) Intra-tumoral dendritic cells increase efficacy of peripheral vaccination by modulation of glioma microenvironment. Neuro Oncol 12:377–388

    Article  PubMed  CAS  Google Scholar 

  27. Boniface K, Blumenschein WM, Brovont-Porth K, McGeachy MJ, Basham B, Desai B, Pierce R, McClanahan TK, Sadekova S, de Waal Malefyt R (2010) Human Th17 cells comprise heterogeneous subsets including IFN-gamma-producing cells with distinct properties from the Th1 lineage. J Immunol 185:679–687

    Article  PubMed  CAS  Google Scholar 

  28. Gorelik L, Constant S, Flavell RA (2002) Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med 195:1499–1505

    Article  PubMed  CAS  Google Scholar 

  29. 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 

  30. Numasaki M, Watanabe M, Suzuki T, Takahashi H, Nakamura A, McAllister F, Hishinuma T, Goto J, Lotze MT, Kolls JK, Sasaki H (2005) IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. J Immunol 175:6177–6189

    PubMed  CAS  Google Scholar 

  31. 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 

  32. Kryczek I, Wei S, Szeliga W, Vatan L, Zou W (2009) Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood 114:357–359

    Article  PubMed  CAS  Google Scholar 

  33. Ngiow SF, Smyth MJ, Teng MW (2010) Does IL-17 suppress tumor growth? Blood 115:2554–2555 author reply 2556–2557

    Article  PubMed  CAS  Google Scholar 

  34. Weaver CT, Hatton RD (2009) Interplay between the TH17 and TReg cell lineages: a (co-)evolutionary perspective. Nat Rev Immunol 9:883–889

    Article  PubMed  CAS  Google Scholar 

  35. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317:256–260

    Article  PubMed  CAS  Google Scholar 

  36. Kehlen A, Thiele K, Riemann D, Rainov N, Langner J (1999) Interleukin-17 stimulates the expression of IkappaB alpha mRNA and the secretion of IL-6 and IL-8 in glioblastoma cell lines. J Neuroimmunol 101:1–6

    Article  PubMed  CAS  Google Scholar 

  37. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964

    Article  PubMed  CAS  Google Scholar 

  38. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen YT, Ohtani H, Old LJ, Odunsi K (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102:18538–18543

    Article  PubMed  CAS  Google Scholar 

  39. He D, Li H, Yusuf N, Elmets CA, Li J, Mountz JD, Xu H (2010) IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cells. J Immunol 184:2281–2288

    Article  PubMed  CAS  Google Scholar 

  40. Suryani S, Sutton I (2007) An interferon-gamma-producing Th1 subset is the major source of IL-17 in experimental autoimmune encephalitis. J Neuroimmunol 183:96–103

    Article  PubMed  CAS  Google Scholar 

  41. Nam JS, Terabe M, Kang MJ, Chae H, Voong N, Yang YA, Laurence A, Michalowska A, Mamura M, Lonning S, Berzofsky JA, Wakefield LM (2008) Transforming growth factor beta subverts the immune system into directly promoting tumor growth through interleukin-17. Cancer Res 68:3915–3923

    Article  PubMed  CAS  Google Scholar 

  42. Ifergan I, Kebir H, Bernard M, Wosik K, Dodelet-Devillers A, Cayrol R, Arbour N, Prat A (2008) The blood-brain barrier induces differentiation of migrating monocytes into Th17-polarizing dendritic cells. Brain 131:785–799

    Article  PubMed  Google Scholar 

  43. 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 

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Acknowledgments

We thank Ileana Zucca for collaboration in Magnetic Resonance Imaging, Dr. Alberto Gobbi and Emiko Kazama for help with mice shipment. This work has been supported by a grant from Il Fondo di Gio, a charity affiliated to the International Brain Tumor Alliance and by funds from the Italian Minister of Health.

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Unit of Molecular Neuro-Oncology, Fondazione I.R.C.C.S. Istituto Neurologico C. Besta, via Celoria 11, 20133, Milan, Italy

    Gabriele Cantini, Federica Pisati, Véronique Frattini, Gaetano Finocchiaro & Serena Pellegatta

  2. Unit of Scientific Direction, Experimental Magnetic Resonance, Fondazione I.R.C.C.S. Istituto Neurologico C. Besta, via Celoria 11, 20133, Milan, Italy

    Alfonso Mastropietro

  3. Department of Experimental Oncology, IFOM-IEO Campus, via Adamello 16, 20139, Milan, Italy

    Gabriele Cantini, Federica Pisati, Véronique Frattini, Gaetano Finocchiaro & Serena Pellegatta

  4. Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Yoichiro Iwakura

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  1. Gabriele Cantini
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  2. Federica Pisati
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Correspondence to Serena Pellegatta.

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Cantini, G., Pisati, F., Mastropietro, A. et al. A critical role for regulatory T cells in driving cytokine profiles of Th17 cells and their modulation of glioma microenvironment. Cancer Immunol Immunother 60, 1739–1750 (2011). https://doi.org/10.1007/s00262-011-1069-4

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  • DOI: https://doi.org/10.1007/s00262-011-1069-4

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