Skip to main content
SpringerLink
Log in

High density of IL-17-producing cells is associated with improved prognosis for advanced epithelial ovarian cancer

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Interleukin (IL)-17 is the signature cytokine of T helper 17 cells. The role of IL-17 in the tumor microenvironment is still controversial. Few studies describing IL-17 expression in ovarian cancer have been reported. We have therefore analyzed the in situ tumor expression of IL-17 in advanced ovarian cancer and the possible correlation of IL-17 expression with tumor-associated macrophages (TAMs) and with survival in advanced ovarian cancer. Clinical data of 104 patients with stage III–IV epithelial ovarian cancer at the Sun Yat-sen University Cancer Center between 2000 and 2008 were retrospectively reviewed. Immunohistochemical staining of IL-17 and CD163 (marker for TAMs) was performed. Our data showed that levels of IL-17 were significantly increased in ovarian cancer compared with normal ovarian tissues (P<0.001). The high IL-17 expression group included more patients with grade 1 tumors than the low IL-17 expression group (P=0.042). High IL-17 expression correlated with improved progression-free survival (PFS) in advanced ovarian cancer (P<0.001). However, no significant difference was observed in overall survival between the high and low IL-17 expression groups. Multivariate analysis revealed that the density of IL-17-producing cells was a positive prognostic factor for PFS (P=0.001). Moreover, a positive correlation between the density of IL-17-producing cells and TAMs was identified (r=0.354, P<0.001). Our results indicate that the infiltration of IL-17-producing cells might contribute to improved PFS in advanced ovarian cancer. Our findings provide a new insight into the complex role of IL-17 in the tumor microenvironment of ovarian cancer.

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

Similar content being viewed by others

References

  • Benchetrit F, Ciree A, Vives V, Warnier G, Gey A, Sautès-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 

  • Bettelli E, Korn T, Oukka M, Kuchroo VK (2008) Induction and effector functions of T(H)17 cells. Nature 453:1051–1057

    Article  PubMed  CAS  Google Scholar 

  • Brun JL, Feyler A, Chêne G, Saurel J, Brun G, Hocké C (2000) Long-term results and prognostic factors in patients with epithelial ovarian cancer. Gynecol Oncol 78:21–27

    Article  PubMed  CAS  Google Scholar 

  • Chabaud M, Fossiez F, Taupin JL, Miossec P (1998) Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines. J Immunol 161:409–414

    PubMed  CAS  Google Scholar 

  • Clear AJ, Lee AM, Calaminici M, Ramsay AG, Morris KJ, Hallam S, Kelly G, Macdougall F, Lister TA, Gribben JG (2010) Increased angiogenic sprouting in poor prognosis FL is associated with elevated numbers of CD163+ macrophages within the immediate sprouting microenvironment. Blood 115:5053–5056

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès 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 

  • Gu FM, Li QL, Gao Q, Jiang JH, Zhu K, Huang XY, Pan JF, Yan J, Hu JH, Wang Z, Dai Z, Fan J, Zhou J (2011) IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma. Mol Cancer 10:150

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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 

  • Hu M, Polyak K (2008) Microenvironmental regulation of cancer development. Curr Opin Genet Dev 18:27–34

    Article  PubMed  CAS  Google Scholar 

  • Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  • Jovanovic DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, Zhang M, Mineau F, Pelletier JP (1998) IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol 160:3513–3521

    PubMed  CAS  Google Scholar 

  • Kato T, Furumoto H, Ogura T, Onishi Y, Irahara M, Yamano S, Kamada M, Aono T (2001) Expression of IL-17 mRNA in ovarian cancer. Biochem Biophys Res Commun 282:735–738

    Article  PubMed  CAS  Google Scholar 

  • Kennedy R, Celis E (2008) Multiple roles for CD4+ T cells in anti-tumor immune responses. Immunol Rev 222:129–144

    Article  PubMed  CAS  Google Scholar 

  • Komohara Y, Hasita H, Ohnishi K, Fujiwara Y, Suzu S, Eto M, Takeya M (2011) Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma. Cancer Sci 102:1424–1431

    Article  PubMed  CAS  Google Scholar 

  • Korn T, Oukka M, Kuchroo V, Bettelli E (2007) Th17 cells: effector T cells with inflammatory properties. Semin Immunol 19:362–371

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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 

  • 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 

  • Kurahara H, Shinchi H, Mataki Y, Maemura K, Noma H, Kubo F, Sakoda M, Ueno S, Natsugoe S, Takao S (2011) Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res 167:e211–e219

    Article  PubMed  Google Scholar 

  • Kurman RJ, Shih IM (2010) The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 34:433–443

    Article  PubMed  Google Scholar 

  • Lan C, Huang X, Lin S, Huang H, Cai Q, Wan T, Lu J, Liu J (2012) Expression of M2-polarized macrophages is associated with poor prognosis for advanced epithelial ovarian cancer. Technol Cancer Res Treat. doi:10.7785/tcrt.2012.500312

  • 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 

  • Mbeunkui F, Johann DJ Jr (2009) Cancer and the tumor microenvironment: a review of an essential relationship. Cancer Chemother Pharmacol 63:571–582

    Article  PubMed  Google Scholar 

  • 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 

  • Muranski P, Restifo NP (2009) Adoptive immunotherapy of cancer using CD4(+) T cells. Curr Opin Immunol 21:200–208

    Article  PubMed  CAS  Google Scholar 

  • Ness RB, Cottreau C (1999) Possible role of ovarian epithelial inflammation in ovarian cancer. J Natl Cancer Inst 91:1459–1467

    Article  PubMed  CAS  Google Scholar 

  • Niino D, Komohara Y, Murayama T, Aoki R, Kimura Y, Hashikawa K, Kiyasu J, Takeuchi M, Suefuji N, Sugita Y, Takeya M, Ohshima K (2010) Ratio of M2 macrophage expression is closely associated with poor prognosis for angioimmunoblastic T-cell lymphoma (AITL). Pathol Int 60:278–283

    Article  PubMed  Google Scholar 

  • 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 

  • Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570

    Article  PubMed  CAS  Google Scholar 

  • Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42:717–727

    Article  PubMed  CAS  Google Scholar 

  • Silva-Santos B (2010) Promoting angiogenesis within the tumor microenvironment: the secret life of murine lymphoid IL-17-producing gammadelta T cells. Eur J Immunol 40:1873–1876

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Tartour E, Fossiez F, Joyeux I, Galinha A, Gey A, Claret E, Sastre-Garau X, Couturier J, Mosseri V, Vives V, Banchereau J, Fridman WH, Wijdenes J, Lebecque S, Sautès-Fridman C (1999) Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Res 59:3698–3704

    PubMed  CAS  Google Scholar 

  • Wakita D, Sumida K, Iwakura Y, Nishikawa H, Ohkuri T, Chamoto K, Kitamura H, Nishimura T (2010) Tumor-infiltrating IL-17-producing gammadelta T cells support the progression of tumor by promoting angiogenesis. Eur J Immunol 40:1927–1937

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Witz IP (2009) The tumor microenvironment: the making of a paradigm. Cancer Microenviron 2 (Suppl 1):9–17

    Article  PubMed  Google Scholar 

  • Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM (2009) Malignant B cells skew the balance of regulatory T cells and TH17 cells in B-cell non-Hodgkin’s lymphoma. Cancer Res 69:5522–5530

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Zhang JP, Yan J, Xu J, Pang XH, Chen MS, Li L, Wu C, Li SP, Zheng L (2009) Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol 50:980–989

    Article  PubMed  CAS  Google Scholar 

  • Zhu X, Mulcahy LA, Mohammed RA, Lee AH, Franks HA, Kilpatrick L, Yilmazer A, Paish EC, Ellis IO, Patel PM, Jackson AM (2008) IL-17 expression by breast-cancer-associated macrophages: IL-17 promotes invasiveness of breast cancer cell lines. Breast Cancer Res 10:R95

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Medical Scientific Research Foundation of Guangdong Province (B2012133).

Conflict of interest

The authors declare that there are no conflicts of interest.

Author information

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Department of Gynecologic Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China

    Chunyan Lan, Xin Huang & Jihong Liu

  2. State Key Laboratory of Oncology in South China, Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China

    Suxia Lin & Jiabin Lu

  3. State Key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China

    Huiqiang Huang & Qichun Cai

Authors
  1. Chunyan Lan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suxia Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huiqiang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qichun Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jiabin Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jihong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jihong Liu.

Additional information

Chunyan Lan and Xin Huang contributed equally to the manuscript.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 63 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lan, C., Huang, X., Lin, S. et al. High density of IL-17-producing cells is associated with improved prognosis for advanced epithelial ovarian cancer. Cell Tissue Res 352, 351–359 (2013). https://doi.org/10.1007/s00441-013-1567-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-013-1567-0

Keywords

Search

Navigation