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

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.