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

Cancer Immunol Immunother. 2012 Nov;61(11):1965-75. doi: 10.1007/s00262-012-1241-5. Epub 2012 Apr 13.

Abstract

IL-22-producing CD4(+) T cells (IL-22(+)CD4(+) T cells) and Th22 cells (IL-22(+)IL-17(-)IFN-γ(-)CD4(+) 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-17(-)CD4(+), IL-22(+)IFN-γ(+)CD4(+), IL-22(+)IFN-γ(-)CD4(+), 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Polarity / immunology
  • Cells, Cultured
  • Coculture Techniques
  • Disease Progression
  • Female
  • Humans
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Interleukin-17 / immunology
  • Interleukin-23 / immunology
  • Interleukin-6 / immunology
  • Interleukins / immunology*
  • Lipopolysaccharide Receptors / immunology
  • Male
  • Middle Aged
  • Monocytes / immunology
  • Stomach Neoplasms / immunology*
  • Stomach Neoplasms / mortality

Substances

  • IL6 protein, human
  • Interleukin-17
  • Interleukin-23
  • Interleukin-6
  • Interleukins
  • Lipopolysaccharide Receptors
  • Interferon-gamma
  • interleukin-22