Increased Circulating Th22 and Th17 Cells are Associated with Tumor Progression and Patient Survival in Human Gastric Cancer

Abstract

Although Th22 and Th17 cells have been reported to play critical roles during autoimmunity and inflammation, information on their role in cancer-immunity is limited. In this study, we investigated clinical relevance of circulating Th22 and Th17 cells in patients with gastric cancer (GC). Using multi-color flow cytometry and PMA stimulation, we determined the levels of Th22, Th17 and Th1 cells in the peripheral blood of 32 GC patients and 19 healthy donors, and evaluated their correlations with tumor stage and overall survival. Compared with healthy donors, the frequencies of circulating CD4(+)IL-22(+) T cells, CD4(+)IL-17(+) T cells, Th22 (CD4(+)IL-22(+)IL-17(-)INF-γ(-)) cells, Th17 (CD4(+)IL-17(+)INF-γ(-)) cells were increased in patients with GC, but there was no significant differences in the frequencies of CD4(+)IFN-γ(+) T cells and Th1 (CD4(+)IL-17(-)INF-γ(+)) cells. Th22 cells showed positive correlation with Th17 cells and CD4(+)IL-17(+) T cells in patients with GC. Furthermore, the frequencies of Th22 and Th17 cells were significantly higher in stage III-IV GC patients versus stage I-II and correlated with patients' overall survival. These data suggest that circulating Th22 cells as well as Th17 cells are increased in the peripheral blood of GC patients with tumor progression, and that these cells may be promising novel clinical markers for 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].…”

B7-H1–expressing antigen-presenting cells mediate polarization of protumorigenic Th22 subsets

“…Studies have identified a subset of epithelial Th effector cells that produce IL-22 (and are thus designated Th22) (9,21), and it has been suggested that these cells participate in adaptive immunity and reorganization of epithelia via IL-22-mediated induction of antimicrobial peptides and genes involved in keratinocyte differentiation (27). In our investigation, the substantial proportion of Th22 cells in peritumoral liver and tumor tissues from HCC patients also secreted IFN-γ and/or IL-17, and reports have described such plasticity in other T cell phenotypes as well: for example, Th17 cells expressing IFN-γ and Tregs expressing IL-17 (28)(29)(30)(31).…”

“…Contrary to the infiltration pattern of the entire Th22 cell population, the proportion of PD-1 + Th cells was markedly increased in tumor tissue (60 ± 13%, n = 26; P < 0.001 compared with proportions in blood and peritumoral liver tissue; Figure 5C Protumorigenic role of Th22 and Th17 in HCC. Previous studies have shown that IL-22 exhibits protumorigenic activity in several types of human cancers (21)(22)(23)(24)(25)(26). To evaluate the potential role of IL-22 and its related subsets in HCC pathogenesis, we divided the 26 HCC patients described above into 2 groups according to their complete clinical and pathological characteristics.…”

Hyperactive gp130/STAT3‐driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development

“…Nevertheless, other cytokines linked with the Th17 programme may contribute to lymphoid neogenesis in GC. For example, IL‐22 and IL‐23 have emerged as drivers of lymphoid neogenesis in other inflammatory settings,4, 35, 38 and are linked with human GC progression 30, 46, 47…”