Intra-tumoral IFN-gamma-producing Th22 cells correlate with TNM staging and the worst outcomes in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the 5th leading cause of cancer-related death. The causes of this cancer remain unknown but increasing evidence indicates a key role of the host immuneresponseand cytokines in human carcinogenesis. Intra-tumoral IL-22 levels have been shown to be elevated in PDAC patients.However,little is known regarding the expression and clinical relevanceof Th22 cells in human PDAC and, furthermore, which tumor-infiltrating lymphocytes (TILs) are the main producersof IL-22 isunknown. In this study, we characterized the functional proprieties of the different subsets of IL-22-producing TILs and analyzed their relationship with the TNM staging system and patient survival. We have demonstrated for the first time that, in PDAC patients, the T cells co-producing IFN-γ and exertingperforin-mediated cytotoxicity are the major intra-tumoral source of IL-22. In addition, isolated Th22 cells were able to induce apoptosis, which was antagonized by IL-22. Finally, we observed that the IL-22-producing T cells were significantly increased in tumor tissue and that this increase was positively correlated with TNM staging of PDAC and poorer patient survival. These novel findings support the dual role of the anti-tumor immune system and that IL-22-producing cells may participate in PDAC pathogenesis. Therefore, monitoring Th22 levels could be a good diagnostic parameter and blocking IL-22 signaling may represent a viable method for anti-PDAC therapies.