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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

Abstract

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.

Keywords

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

Notes

Acknowledgments

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)

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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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