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Increased Circulating Th22 and Th17 Cells are Associated with Tumor Progression and Patient Survival in Human Gastric Cancer

Journal of Clinical Immunology volume 32, pages 1332–1339 (2012)Cite this article

Abstract

Although Th22 and Th17 cells have been reported to play critical roles during autoimmunity and inflammation, information on their role in cancer-immunity is limited. In this study, we investigated clinical relevance of circulating Th22 and Th17 cells in patients with gastric cancer (GC). Using multi-color flow cytometry and PMA stimulation, we determined the levels of Th22, Th17 and Th1 cells in the peripheral blood of 32 GC patients and 19 healthy donors, and evaluated their correlations with tumor stage and overall survival. Compared with healthy donors, the frequencies of circulating CD4+IL-22+ T cells, CD4+IL-17+ T cells, Th22 (CD4+IL-22+IL-17-INF-γ−) cells, Th17 (CD4+IL-17+INF-γ−) cells were increased in patients with GC, but there was no significant differences in the frequencies of CD4+IFN-γ+ T cells and Th1 (CD4+IL-17−INF-γ+) cells. Th22 cells showed positive correlation with Th17 cells and CD4+IL-17+ T cells in patients with GC. Furthermore, the frequencies of Th22 and Th17 cells were significantly higher in stage III–IV GC patients versus stage I–II and correlated with patients’ overall survival. These data suggest that circulating Th22 cells as well as Th17 cells are increased in the peripheral blood of GC patients with tumor progression, and that these cells may be promising novel clinical markers for GC.

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References

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

    PubMed  Article  Google Scholar 

  2. Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–41.

    PubMed  Article  CAS  Google Scholar 

  3. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6:1123–32.

    PubMed  Article  CAS  Google Scholar 

  4. Dhodapkar KM, Barbuto S, Matthews P, Kukreja A, Mazumder A, Vesole D, Jagannath S, Dhodapkar MV. Dendritic cells mediate the induction of polyfunctional human IL17-producing cells (Th17-1 cells) enriched in the bone marrow of patients with myeloma. Blood. 2008;112:2878–85.

    PubMed  Article  CAS  Google Scholar 

  5. Zhang JP, Yan J, Xu J, Pang XH, Chen MS, Li L, Wu C, Li SP, Zheng L. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol. 2009;50:980–9.

    PubMed  Article  CAS  Google Scholar 

  6. Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM. Malignant B cells skew the balance of regulatory T cells and TH17 cells in B-cell non-Hodgkin’s lymphoma. Cancer Res. 2009;69:5522–30.

    PubMed  Article  CAS  Google Scholar 

  7. Derhovanessian E, Adams V, Hahnel K, Groeger A, Pandha H, Ward S, Pawelec G. 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. 2009;125:1372–9.

    PubMed  Article  CAS  Google Scholar 

  8. Kryczek I, Banerjee M, Cheng P, et al. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood. 2009;114:1141–9.

    PubMed  Article  CAS  Google Scholar 

  9. Iida T, Iwahashi M, Katsuda M, et al. Tumor-infiltrating CD4+ Th17 cells produce IL-17 in tumor microenvironment and promote tumor progression in human gastric cancer. Oncol Rep. 2011;25:1271–7.

    PubMed  Article  CAS  Google Scholar 

  10. Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol. 2009;10:857–63.

    PubMed  Article  CAS  Google Scholar 

  11. Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol. 2009;10:864–71.

    PubMed  Article  CAS  Google Scholar 

  12. Eyerich S, Eyerich K, Pennino D, et al. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest. 2009;119:3573–85.

    PubMed  CAS  Google Scholar 

  13. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature. 2008;453:106–9.

    PubMed  Article  CAS  Google Scholar 

  14. Nograles KE, Zaba LC, Shemer A, et al. IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J Allergy Clin Immunol. 2009;123(1244–52):e2.

    PubMed  Google Scholar 

  15. Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A. Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol. 2010;130:1373–83.

    PubMed  Article  CAS  Google Scholar 

  16. Qin WZ, Chen LL, Pan HF, et al. Expressions of IL-22 in circulating CD4+/CD8+ T cells and their correlation with disease activity in SLE patients. Clin Exp Med. 2011;11:245–50.

    PubMed  Article  CAS  Google Scholar 

  17. Zhang L, Li JM, Liu XG, et al. Elevated Th22 cells correlated with Th17 cells in patients with rheumatoid arthritis. J Clin Immunol. 2011;31:606–14.

    PubMed  Article  CAS  Google Scholar 

  18. Zhang W, Chen Y, Wei H, Zheng C, Sun R, Zhang J, Tian Z. Antiapoptotic activity of autocrine interleukin-22 and therapeutic effects of interleukin-22-small interfering RNA on human lung cancer xenografts. Clin Cancer Res. 2008;14:6432–9.

    PubMed  Article  CAS  Google Scholar 

  19. Jiang R, Tan Z, Deng L, Chen Y, Xia Y, Gao Y, Wang X, Sun B (2011) Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology

  20. Zhang B, Rong G, Wei H, et al. The prevalence of Th17 cells in patients with gastric cancer. Biochem Biophys Res Commun. 2008;374:533–7.

    PubMed  Article  CAS  Google Scholar 

  21. Maruyama T, Kono K, Mizukami Y, Kawaguchi Y, Mimura K, Watanabe M, Izawa S, Fujii H. Distribution of Th17 cells and FoxP3(+) regulatory T cells in tumor-infiltrating lymphocytes, tumor-draining lymph nodes and peripheral blood lymphocytes in patients with gastric cancer. Cancer Sci. 2010;101:1947–54.

    PubMed  Article  CAS  Google Scholar 

  22. Szaflarska A, Szczepanik A, Siedlar M, Czupryna A, Sierzega M, Popiela T, Zembala M. Preoperative plasma level of IL-10 but not of proinflammatory cytokines is an independent prognostic factor in patients with gastric cancer. Anticancer Res. 2009;29:5005–12.

    PubMed  CAS  Google Scholar 

  23. Yuan XL, Chen L, Zhang TT, Ma YH, Zhou YL, Zhao Y, Wang WW, Dong P, Yu L, Zhang YY, Shen LS. Gastric cancer cells induce human CD4 + Foxp3+ regulatory T cells through the production of TGF-β1. World J Gastroenterol. 2011;17:2019–27.

    PubMed  Article  CAS  Google Scholar 

  24. Zenewicz LA, Flavell RA. Recent advances in IL-22 biology. Int Immunol. 2011;23:159–63.

    PubMed  Article  CAS  Google Scholar 

  25. Wolk K, Kunz S, Asadullah K, Sabat R. Cutting edge: immune cells as sources and targets of the IL-10 family members? J Immunol. 2002;168:5397–402.

    PubMed  CAS  Google Scholar 

  26. Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, Fouser LA. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med. 2006;203:2271–9.

    PubMed  Article  CAS  Google Scholar 

  27. Chung Y, Yang X, Chang SH, Ma L, Tian Q, Dong C. Expression and regulation of IL-22 in the IL-17-producing CD4+ T lymphocytes. Cell Res. 2006;16:902–7.

    PubMed  Article  CAS  Google Scholar 

  28. Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, Ouyang W. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature. 2007;445:648–51.

    PubMed  Article  CAS  Google Scholar 

  29. Fujita H, Nograles KE, Kikuchi T, Gonzalez J, Carucci JA, Krueger JG. Human Langerhans cells induce distinct IL-22-producing CD4+ T cells lacking IL-17 production. Proc Natl Acad Sci USA. 2009;106:21795–800.

    PubMed  Article  CAS  Google Scholar 

  30. Wang SK, Zhu HF, He BS, Zhang ZY, Chen ZT, Wang ZZ, Wu GL. CagA + H pylori infection is associated with polarization of T helper cell immune responses in gastric carcinogenesis. World J Gastroenterol. 2007;13:2923–31.

    PubMed  CAS  Google Scholar 

  31. Mangan PR, Harrington LE, O’Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006;441:231–4.

    PubMed  Article  CAS  Google Scholar 

  32. Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ. Gastric cancer. Lancet. 2009;374:477–90.

    PubMed  Article  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (NSFC, No. 81071412) and National Basic Research Program of China (973 program, No. 2009CB522606).

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The authors declare no conflict of interest.

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Affiliations

  1. Department of Clinical Microbiology and Immunology, College of Medical Laboratory Science, Third Military Medical University, No.30 Gaotanyan street, Chongqing, 400038, People’s Republic of China

    Tao Liu, Liusheng Peng, Yun Shi, Xuhu Mao, Ping Cheng, Tingting Wang, Na Chen, Jinyu Zhang, Xiaofei Liu, Na Li, Gang Guo, Wende Tong, Yuan Zhuang & Quanming Zou

  2. Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, No.30 Gaotanyan street, Chongqing, 400038, People’s Republic of China

    Peiwu Yu & Yongliang Zhao

  3. School of Molecular Science, La Trobe University, Bundoora, Victoria, 3085, Australia

    Weisan Chen

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  1. Tao Liu
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  2. Liusheng Peng
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  16. Yuan Zhuang
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  17. Quanming Zou
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Corresponding authors

Correspondence to Yuan Zhuang or Quanming Zou.

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Tao Liu and Liusheng Peng contributed equally to the work.

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Supplemental Fig. 1

Cytokine detection in sera. The level of TGF-β1 (a) IL-10 (b) in sera of GC patients and healthy donors were determined by ELISA. CPB, cancer peripheral blood; HPB, healthy peripheral blood; Data were expressed as box plots, in which the horizontal lines illustrate the 25th, 50th, and 75th percentiles. Vertical lines represented the min and max. Significance between two groups was indicated by P value; P < 0.05 was considered significant. (TIFF 7671 kb)

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Liu, T., Peng, L., Yu, P. et al. Increased Circulating Th22 and Th17 Cells are Associated with Tumor Progression and Patient Survival in Human Gastric Cancer. J Clin Immunol 32, 1332–1339 (2012). https://doi.org/10.1007/s10875-012-9718-8

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  • DOI: https://doi.org/10.1007/s10875-012-9718-8

Keywords

  • Th22 cells
  • Th17 cells
  • gastric cancer
  • tumor progression
  • tumor survival