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.
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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).
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262_2012_1241_MOESM1_ESM.tif
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
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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Zhuang, Y., Peng, Ls., Zhao, Yl. et al. Increased intratumoral IL-22-producing CD4+ T cells and Th22 cells correlate with gastric cancer progression and predict poor patient survival. Cancer Immunol Immunother 61, 1965–1975 (2012). https://doi.org/10.1007/s00262-012-1241-5
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DOI: https://doi.org/10.1007/s00262-012-1241-5