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

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.

Emerging Role of Interleukins in Cancer Treatment

“…Observations on gastric, colon and pancreas cancer have shown correlation between increased number of IL-22producing T lymphocytes and advanced stage of cancer and its negative impact on patients' overall survival. IL-22 level was also elevated in chemoresistant colon cancer cases [172][173][174]. Similar observations have been reported in liver cancer, and non-small cell lung cancer [168,175].…”

DNAX-activating Protein 10 (DAP10) Membrane Adaptor Associates with Receptor for Advanced Glycation End Products (RAGE) and Modulates the RAGE-triggered Signaling Pathway in Human Keratinocytes

“…IL-22 produced by infiltrating T cells and cancer cells themselves stimulates cell proliferation and enhances survival (54,55). In addition, S100A8/A9, RAGE, and DAP10 are often overexpressed in various types of cancer (30, 56 -59).…”

Th22 cells increase in poor prognosis multiple myeloma and promote tumor cell growth and survival

“…26 Th22 differentiation requires tumor necrosis factor a (TNFa) and IL-6, and pDCs drive Th22 polarization through secretion of those cytokines. 18 Interestingly, pDCs were found to be increased in the BM of MM patients compared with normal donors.…”