Journal of Cancer Research and Clinical Oncology

, Volume 139, Issue 8, pp 1295–1302 | Cite as

High IL-17-positive tumor immune cell infiltration is indicative for chemosensitivity of ovarian carcinoma

  • Raoul A. Droeser
  • Uwe Güth
  • Serenella Eppenberger-Castori
  • Sylvia Stadlmann
  • Christian Hirt
  • Luigi Terracciano
  • Gad Singer
Original Paper

Abstract

Purpose

Ovarian carcinoma in most instances is diagnosed in an advanced stage which cannot be cured by surgical tumor debulking alone. Standard adjuvant chemotherapy usually follows surgical procedures. Yet, few reliable predictive tissue markers exist for the response of ovarian carcinoma to chemotherapy. In this study, we evaluated the predictive value of IL-17- and FOXP3-positive tumor immune cell infiltration (TICI) for response to chemotherapy in ovarian carcinoma.

Methods

Formalin fixed and paraffin embedded biopsies of mostly high-grade primary serous ovarian carcinomas and their matched recurrences were immunostained with IL-17 and FOXP3 on a tissue microarray. Chemoresistance was defined as tumor recurrence within 6 months of the completion of platinum-based chemotherapy. In 94 and 90 biopsies, conclusive data for IL-17 and FOXP3 were available, respectively.

Results

IL-17, but not FOXP3-positive TICI, displayed a significantly higher density in biopsies of chemosensitive tumors (p = 0.01). No significant difference in the expression of IL-17 and FOXP3 TICI was observed in all paired primary and recurrent biopsies without respect to chemoresponse (p = 0.77 and p = 0.87, respectively). However, significantly more IL-17-positive recurrences were encountered in the group of patients with chemosensitive tumors (p = 0.008).

Conclusions

High IL-17-positive TICI is indicative for response to chemotherapy in ovarian carcinoma. Higher frequency of IL-17-positive TICI might persist in recurrent tumor tissues of chemosensitive biopsies, suggesting repetitive platinum-based chemotherapy as an appropriate therapy for patients with IL-17-positive recurrences.

Keywords

Forkhead box P3 Tissue microarray Regulatory T cell Interleukin-17 Chemosensitivity Ovarian cancer 

Abbreviations

FOXP3

Forkhead box P3

TMA

Tissue microarray

Treg

Regulatory T cell

IL-17

Interleukin-17

Notes

Acknowledgments

This study was funded by the Swiss Cancer League (Oncosuisse), Grant number OCS 01506-02-2004 for G.S.

Conflict of interest

The authors declare that they have no financial competing interests.

References

  1. Ben Shoshan J, Maysel-Auslender S, Mor A, Keren G, George J (2008) Hypoxia controls CD4+ CD25+ regulatory T-cell homeostasis via hypoxia-inducible factor-1alpha. Eur J Immunol 38:2412–2418PubMedCrossRefGoogle Scholar
  2. Bettelli E, Korn T, Oukka M, Kuchroo VK (2008) Induction and effector functions of T(H)17 cells. Nature 453:1051–1057PubMedCrossRefGoogle Scholar
  3. Bray F, Loos AH, Tognazzo S, La VC (2005) Ovarian cancer in Europe: cross-sectional trends in incidence and mortality in 28 countries, 1953–2000. Int J Cancer 113:977–990PubMedCrossRefGoogle Scholar
  4. Charles KA, Kulbe H, Soper R, Escorcio-Correia M, Lawrence T, Schultheis A, Chakravarty P, Thompson RG, Kollias G, Smyth JF, Balkwill FR, Hagemann T (2009) The tumor-promoting actions of TNF-alpha involve TNFR1 and IL-17 in ovarian cancer in mice and humans. J Clin Invest 119:3011–3023PubMedCrossRefGoogle Scholar
  5. Cua DJ, Tato CM (2010) Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol 10:479–489PubMedCrossRefGoogle Scholar
  6. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949PubMedCrossRefGoogle Scholar
  7. de Kruijf EM, van Nes JG, Sajet A, Tummers QR, Putter H, Osanto S, Speetjens FM, Smit VT, Liefers GJ, van de Velde CJ, Kuppen PJ (2010) The predictive value of HLA class I tumor cell expression and presence of intratumoral Tregs for chemotherapy in patients with early breast cancer. Clin Cancer Res 16:1272–1280PubMedCrossRefGoogle Scholar
  8. De Schutter H, Landuyt W, Verbeken E, Goethals L, Hermans R, Nuyts S (2005) The prognostic value of the hypoxia markers CA IX and GLUT 1 and the cytokines VEGF and IL 6 in head and neck squamous cell carcinoma treated by radiotherapy ± chemotherapy. BMC Cancer 5:42PubMedCrossRefGoogle Scholar
  9. Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, von Torne C, Weichert W, Engels K, Solbach C, Schrader I, Dietel M, von Minckwitz G (2010) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28:105–113PubMedCrossRefGoogle Scholar
  10. Ferlay J, Parkin DM, Steliarova-Foucher E (2010) Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 46:765–781PubMedCrossRefGoogle Scholar
  11. 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 313:1960–1964PubMedCrossRefGoogle Scholar
  12. He Z, Gao J, Wang Q, Liu M, Li Y, Li X, Tang H, Zheng J (2008) S100P contributes to chemosensitivity of human ovarian cancer cell line OVCAR3. Oncol Rep 20:325–332PubMedGoogle Scholar
  13. Jazaeri AA, Awtrey CS, Chandramouli GV, Chuang YE, Khan J, Sotiriou C, Aprelikova O, Yee CJ, Zorn KK, Birrer MJ, Barrett JC, Boyd J (2005) Gene expression profiles associated with response to chemotherapy in epithelial ovarian cancers. Clin Cancer Res 11:6300–6310PubMedCrossRefGoogle Scholar
  14. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300PubMedCrossRefGoogle Scholar
  15. Kigawa J, Sato S, Shimada M, Takahashi M, Itamochi H, Kanamori Y, Terakawa N (2001) p53 gene status and chemosensitivity in ovarian cancer. Hum Cell 14:165–171PubMedGoogle Scholar
  16. 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 114:1141–1149PubMedCrossRefGoogle Scholar
  17. Leveque L, Deknuydt F, Bioley G, Old LJ, Matsuzaki J, Odunsi K, Ayyoub M, Valmori D (2009) Interleukin 2-mediated conversion of ovarian cancer-associated CD4+ regulatory T cells into proinflammatory interleukin 17-producing helper T cells. J Immunother 32:101–108PubMedCrossRefGoogle Scholar
  18. Li L, Huang L, Vergis AL, Ye H, Bajwa A, Narayan V, Strieter RM, Rosin DL, Okusa MD (2010) IL-17 produced by neutrophils regulates IFN-gamma-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury. J Clin Invest 120:331–342. doi: 10.1172/JCI38702 PubMedCrossRefGoogle Scholar
  19. Lin AM, Rubin CJ, Khandpur R, Wang JY, Riblett M, Yalavarthi S, Villanueva EC, Shah P, Kaplan MJ, Bruce AT (2011) Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol 187:90–500. doi: 10.4049/jimmunol.1100123 Google Scholar
  20. Liotta LA, Kohn EC (2001) The microenvironment of the tumour-host interface. Nature 411:375–379PubMedCrossRefGoogle Scholar
  21. Menard S, Tomasic G, Casalini P, Balsari A, Pilotti S, Cascinelli N, Salvadori B, Colnaghi MI, Rilke F (1997) Lymphoid infiltration as a prognostic variable for early-onset breast carcinomas. Clin Cancer Res 3:817–819PubMedGoogle Scholar
  22. Minervini A, Di Cristofano C, Gacci M, Serni S, Menicagli M, Lanciotti M, Salinitri G, Rocca CD, Lapini A, Nesi G, Bevilacqua G, Minervini R, Carini M (2008) Prognostic role of histological necrosis for nonmetastatic clear cell renal cell carcinoma: correlation with pathological features and molecular markers. J Urol 180:1284–1289PubMedCrossRefGoogle Scholar
  23. Nosho K, Baba Y, Tanaka N, Shima K, Hayashi M, Meyerhardt JA, Giovannucci E, Dranoff G, Fuchs CS, Ogino S (2010) Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 222:350–366PubMedCrossRefGoogle Scholar
  24. Oble DA, Loewe R, Yu P, Mihm MC Jr (2009) Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human melanoma. Cancer Immun 9:3PubMedGoogle Scholar
  25. Osinsky S, Zavelevich M, Vaupel P (2009) Tumor hypoxia and malignant progression. Exp Oncol 31:80–86PubMedGoogle Scholar
  26. Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666PubMedCrossRefGoogle Scholar
  27. Polcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, Sauerwald A, Keyver-Paik MD, Kubler K, Buttner R, Kuhn WC, Hernando JJ (2010) Foxp3(+) cell infiltration and granzyme B(+)/Foxp3(+) cell ratio are associated with outcome in neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 59:909–919PubMedCrossRefGoogle Scholar
  28. Sato S, Kigawa J, Minagawa Y, Okada M, Shimada M, Takahashi M, Kamazawa S, Terakawa N (1999) Chemosensitivity and p53-dependent apoptosis in epithelial ovarian carcinoma. Cancer 86:1307–1313PubMedCrossRefGoogle Scholar
  29. Sauter G, Simon R, Hillan K (2003) Tissue microarrays in drug discovery. Nat Rev Drug Discov 2:962–972PubMedCrossRefGoogle Scholar
  30. Singer G, Kurman RJ, Chang HW, Cho SK, Shih I (2002) Diverse tumorigenic pathways in ovarian serous carcinoma. Am J Pathol 160:1223–1228PubMedCrossRefGoogle Scholar
  31. Singer G, Oldt R III, Cohen Y, Wang BG, Sidransky D, Kurman RJ, Shih I (2003) Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 95:484–486PubMedCrossRefGoogle Scholar
  32. Stadlmann S, Gueth U, Reiser U, Diener PA, Zeimet AG, Wight E, Mirlacher M, Sauter G, Mihatsch MJ, Singer G (2006) Epithelial growth factor receptor status in primary and recurrent ovarian cancer. Mod Pathol 19:607–610PubMedCrossRefGoogle Scholar
  33. Stadlmann S, Gueth U, Baumhoer D, Moch H, Terracciano L, Singer G (2007a) Glypican-3 expression in primary and recurrent ovarian carcinomas. Int J Gynecol Pathol 26:341–344PubMedCrossRefGoogle Scholar
  34. Stadlmann S, Gueth U, Wight E, Kunz-Schughart LA, Hartmann A, Singer G (2007b) Expression of peroxisome proliferator activated receptor gamma and cyclo-oxygenase 2 in primary and recurrent ovarian carcinoma. J Clin Pathol 60:307–310PubMedCrossRefGoogle Scholar
  35. Stadlmann S, Dirnhofer S, Guth U, Thies S, Singer G (2008) ERCC1-immunoexpression does not predict platinum-resistance in ovarian cancer. Gynecol Oncol 108:252–253PubMedCrossRefGoogle Scholar
  36. Stagg J (2008) Mesenchymal stem cells in cancer. Stem Cell Rev 4:119–124PubMedCrossRefGoogle Scholar
  37. 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 184:1630–1641PubMedCrossRefGoogle Scholar
  38. Takagi S, Chen K, Schwarz R, Iwatsuki S, Herberman RB, Whiteside TL (1989) Functional and phenotypic analysis of tumor-infiltrating lymphocytes isolated from human primary and metastatic liver tumors and cultured in recombinant interleukin-2. Cancer 63:102–111PubMedCrossRefGoogle Scholar
  39. Tang Q, Bluestone JA (2008) The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol 9:239–244PubMedCrossRefGoogle Scholar
  40. Uppaluri R, Dunn GP, Lewis JS Jr (2008) Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in head and neck cancers. Cancer Immun 8:16PubMedGoogle Scholar
  41. Wolf D, Wolf AM, Rumpold H, Fiegl H, Zeimet AG, Muller-Holzner E, Deibl M, Gastl G, Gunsilius E, Marth C (2005) The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res 11:8326–8331PubMedCrossRefGoogle Scholar
  42. Zlobec I, Steele R, Terracciano L, Jass JR, Lugli A (2007) Selecting immunohistochemical cut-off scores for novel biomarkers of progression and survival in colorectal cancer. J Clin Pathol 60:1112–1116. doi: 10.1136/jcp.2006.044537 PubMedCrossRefGoogle Scholar
  43. Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6:295–307PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Raoul A. Droeser
    • 1
    • 2
  • Uwe Güth
    • 3
    • 6
  • Serenella Eppenberger-Castori
    • 4
  • Sylvia Stadlmann
    • 5
  • Christian Hirt
    • 1
    • 2
  • Luigi Terracciano
    • 4
  • Gad Singer
    • 5
  1. 1.Department of SurgeryUniversity Hospital BaselBaselSwitzerland
  2. 2.Institute for Surgical Research and Hospital Management ICFSBaselSwitzerland
  3. 3.Department of Gynecology and ObstetricsUniversity Hospital BaselBaselSwitzerland
  4. 4.Institute of PathologyUniversity Hospital BaselBaselSwitzerland
  5. 5.Institute of PathologyKantonsspital Baden AGBadenSwitzerland
  6. 6.Department of Gynecology and ObstetricsKantonsspital WinterthurWinterthurSwitzerland

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