Cancer Immunology, Immunotherapy

, Volume 61, Issue 11, pp 1965–1975 | Cite as

Increased intratumoral IL-22-producing CD4+ T cells and Th22 cells correlate with gastric cancer progression and predict poor patient survival

  • Yuan Zhuang
  • Liu-sheng Peng
  • Yong-liang Zhao
  • Yun Shi
  • Xu-hu Mao
  • Gang Guo
  • Weisan Chen
  • Xiao-fei Liu
  • Jin-yu Zhang
  • Tao Liu
  • Ping Luo
  • Pei-wu YuEmail author
  • Quan-ming ZouEmail author
Original article


IL-22-producing CD4+ T cells (IL-22+CD4+ T cells) and Th22 cells (IL-22+IL-17IFN-γCD4+ T cells) represent newly discovered T-cell subsets, but their nature, regulation, and clinical relevance in gastric cancer (GC) are presently unknown. In our study, the frequency of IL-22+CD4+ T cells in tumor tissues from 76 GC patients was significantly higher than that in tumor-draining lymph nodes, non-tumor, and peritumoral tissues. Most intratumoral IL-22+CD4+ T cells co-expressed IL-17 and IFN-γ and showed a memory phenotype. Locally enriched IL-22+CD4+ T cells positively correlated with increased CD14+ monocytes and IL-6 and IL-23 detection ex vivo, and in vitro IL-6 and IL-23 induced the polarization of IL-22+CD4+ T cells in a dose-dependent manner and the polarized IL-22+CD4+ T cells co-expressed of IL-17 and IFN-γ. Moreover, IL-22+CD4+ T-cell subsets (IL-22+IL-17+CD4+, IL-22+IL-17CD4+, IL-22+IFN-γ+CD4+, IL-22+IFN-γCD4+, and IL-22+IL-17+IFN-γ+CD4+ T cells), and Th22 cells were also increased in tumors. Furthermore, higher intratumoral IL-22+CD4+ T-cell percentage and Th22-cell percentage were found in patients with tumor-node-metastasis stage advanced and predicted reduced overall survival. In conclusion, our data indicate that IL-22+CD4+ T cells and Th22 cells are likely important in establishing the tumor microenvironment for GC; increased intratumoral IL-22+CD4+ T cells and Th22 cells are associated with tumor progression and predict poorer patient survival, suggesting that tumor-infiltrating IL-22+CD4+ T cells and Th22 cells may be suitable therapeutic targets in patients with GC.


Gastric cancer IL-22+CD4+ T cells Th22 cells Tumor progression Tumor survival 



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

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

262_2012_1241_MOESM1_ESM.tif (4 mb)
IL-22+CD4+ T cells correlate with monocytes, IL-6, and IL-23 in tumors. The correlations and correlation coefficients between the percentage of IL-22+CD4+ T cells in total CD4+ T cells and the percentage of CD14+ monocytes in total CD45+ T cells (a) or the concentrations of IL-6 (b) or IL-23 (c) were evaluated and computed in the same tumors. Each dot represents one patient. (TIFF 4118 kb)
262_2012_1241_MOESM2_ESM.tif (10.6 mb)
IL-22+CD4+ T cells correlate with its IL-17+/IFN-γ+ subsets, Th22 cells, and IL-22+IL-17+IFN-γ+CD4+ T cells in tumors. The correlations and correlation coefficients between the percentages of IL-22+CD4+ T cells and IL-22+IL-17+CD4+ (a), IL-22+IL-17-CD4+ (b), IL-22+IFN-γ+CD4+ (c), IL-22+IFN-γ-CD4+ (d) Th22 (IL-22+IL-17+IFN-γ+CD4+) (e) or IL-22+IL-17+IFN-γ+CD4+ T cells (f) in total CD4+ T cells were evaluated and computed in the same tumors. Each dot represents one patient. (TIFF 10888 kb)


  1. 1.
    Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ (2009) Gastric cancer. Lancet 374:477–490PubMedCrossRefGoogle Scholar
  2. 2.
    Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, Kim WH (2008) Prognostic implications of type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 99:1704–1711PubMedCrossRefGoogle Scholar
  3. 3.
    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 6:1123–1132PubMedCrossRefGoogle Scholar
  4. 4.
    Trifari S, Spits H (2010) IL-22-producing CD4 + T cells: middle-men between the immune system and its environment. Eur J Immunol 40:2369–2371PubMedCrossRefGoogle Scholar
  5. 5.
    Nograles KE, Zaba LC, Shemer A et al (2009) 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 123(e2):1244–1252PubMedCrossRefGoogle Scholar
  6. 6.
    Fujita H, Nograles KE, Kikuchi T, Gonzalez J, Carucci JA, Krueger JG (2009) Human langerhans cells induce distinct IL-22-producing CD4 + T cells lacking IL-17 production. Proc Natl Acad Sci USA 106:21795–21800PubMedCrossRefGoogle Scholar
  7. 7.
    Eyerich S, Eyerich K, Pennino D et al (2009) Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest 119:3573–3585PubMedGoogle Scholar
  8. 8.
    Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H (2009) 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 10:864–871PubMedCrossRefGoogle Scholar
  9. 9.
    Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A (2010) Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol 130:1373–1383PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang L, Li JM, Liu XG et al (2011) Elevated Th22 cells correlated with Th17 cells in patients with rheumatoid arthritis. J Clin Immunol 31:606–614PubMedCrossRefGoogle Scholar
  11. 11.
    Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immuno editing: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570PubMedCrossRefGoogle Scholar
  12. 12.
    Albini A, Sporn MB (2007) The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 7:139–147PubMedCrossRefGoogle Scholar
  13. 13.
    Moser B, Loetscher P (2001) Lymphocyte traffic control by chemokines. Nat Immunol 2:123–128PubMedCrossRefGoogle Scholar
  14. 14.
    Curiel TJ, Wei S, Dong H et al (2003) Blockade of B7–H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 9:562–567PubMedCrossRefGoogle Scholar
  15. 15.
    Zhou G, Drake CG, Levitsky HI (2006) Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines. Blood 107:628–636PubMedCrossRefGoogle Scholar
  16. 16.
    Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605–612PubMedCrossRefGoogle Scholar
  17. 17.
    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 185:1544–1549PubMedCrossRefGoogle Scholar
  18. 18.
    Dumoutier L, Louahed J, Renauld JC (2000) Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. J Immunol 164:1814–1819PubMedGoogle Scholar
  19. 19.
    Sakamoto T, Saito H, Tatebe S, Tsujitani S, Ozaki M, Ito H, Ikeguchi M (2006) Interleukin-10 expression significantly correlates with minor CD8 + T-cell infiltration and high microvessel density in patients with gastric cancer. Int J Cancer 118:1909–1914PubMedCrossRefGoogle Scholar
  20. 20.
    Yan S, Zhang H, Xie Y, Sheng W, Xiang J, Ye Z, Chen W, Yang J (2010) Recombinant human interleukin-24 suppresses gastric carcinoma cell growth in vitro and in vivo. Cancer Invest 28:85–93PubMedCrossRefGoogle Scholar
  21. 21.
    Szaflarska A, Szczepanik A, Siedlar M, Czupryna A, Sierzega M, Popiela T, Zembala M (2009) Preoperative plasma level of IL-10 but not of proinflammatory cytokines is an independent prognostic factor in patients with gastric cancer. Anticancer Res 29:5005–5012PubMedGoogle Scholar
  22. 22.
    Gurney AL (2004) IL-22, a Th1 cytokine that targets the pancreas and select other peripheral tissues. Int Immunopharmacol 4:669–677PubMedCrossRefGoogle Scholar
  23. 23.
    Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, Fouser LA (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203:2271–2279PubMedCrossRefGoogle Scholar
  24. 24.
    Kreymborg K, Etzensperger R, Dumoutier L, Haak S, Rebollo A, Buch T, Heppner FL, Renauld JC, Becher B (2007) IL-22 is expressed by Th17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis. J Immunol 179:8098–8104PubMedGoogle Scholar
  25. 25.
    Wakita D, Chamoto K, Ohkuri T, Narita Y, Ashino S, Sumida K, Nishikawa H, Shiku H, Togashi Y, Kitamura H, Nishimura T (2009) IFN-gamma-dependent type 1 immunity is crucial for immunosurveillance against squamous cell carcinoma in a novel mouse carcinogenesis model. Carcinogenesis 30:1408–1415PubMedCrossRefGoogle Scholar
  26. 26.
    Prabhala RH, Pelluru D, Fulciniti M, Prabhala HK, Nanjappa P, Song W, Pai C, Amin S, Tai YT, Richardson PG, Ghobrial IM, Treon SP, Daley JF, Anderson KC, Kutok JL, Munshi NC (2010) Elevated IL-17 produced by TH17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma. Blood 115:5385–5392PubMedCrossRefGoogle Scholar
  27. 27.
    Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q, Abbas AR, Modrusan Z, Ghilardi N, de Sauvage FJ, Ouyang W (2008) Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 14:282–289PubMedCrossRefGoogle Scholar
  28. 28.
    Xie MH, Aggarwal S, Ho WH, Foster J, Zhang Z, Stinson J, Wood WI, Goddard AD, Gurney AL (2000) Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. J Biol Chem 275:31335–31339PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Yuan Zhuang
    • 1
  • Liu-sheng Peng
    • 1
  • Yong-liang Zhao
    • 2
  • Yun Shi
    • 1
  • Xu-hu Mao
    • 1
  • Gang Guo
    • 1
  • Weisan Chen
    • 3
  • Xiao-fei Liu
    • 1
  • Jin-yu Zhang
    • 1
  • Tao Liu
    • 1
  • Ping Luo
    • 1
  • Pei-wu Yu
    • 2
    Email author
  • Quan-ming Zou
    • 1
    Email author
  1. 1.Department of Clinical Microbiology and Immunology, College of Medical Laboratory ScienceThird Military Medical UniversityChongqingPeople’s Republic of China
  2. 2.Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest HospitalThird Military Medical UniversityChongqingPeople’s Republic of China
  3. 3.Ludwig Institute for Cancer ResearchAustin HospitalHeidelbergAustralia

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