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

Abstract

PDAC (pancreatic ductal adenocarcinoma) is the fifth leading cause of cancer-related death. The causes of this cancer remain unknown, but increasing evidence indicates a key role of the host immune response and cytokines in human carcinogenesis. Intra-tumoral IL (interleukin)-22 levels have been shown to be elevated in PDAC patients. However, little is known regarding the expression and clinical relevance of Th22 cells in human PDAC and, furthermore, which TILs (tumour-infiltrating lymphocytes) are the main producers of IL-22 is unknown. In the present study, we characterized the functional proprieties of the different subsets of IL-22-producing TILs and analysed 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 (interferon γ) and exerting perforin-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 tumour 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-tumour 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 signalling may represent a viable method for anti-PDAC therapies.

The mutual interplay of gut microbiota, diet and human disease

“…Besides, microbiota‐derived tryptophan metabolites have the ability to modulate the AhR‐IL‐22 axis, thus impacting mucosal immune homeostasis in the gut . Importantly, high expression of IL‐22 has been detected in tumour tissues and it has been correlated with cancer progression and poorer patient survival in pancreatic ductal adenocarcinoma . Therefore, dietary‐induced modifications of host metabolomics and the presence of environmental contaminants may alter physiological homeostasis, impacting host fitness and leading to inflammatory responses.…”

The Dark Side of IFN-γ: Its Role in Promoting Cancer Immunoevasion

“…Such cells are natural killer T cells (NKT), which express αβ TCR and NK cell receptors, and innate-like γδ T cells, whose antigen recognition by γδ TCR- is not restricted to major histocompatibility complex (MHC) molecules [ 13 , 14 ]. Th22 IFN-γ + CD4 + T cells, macrophages, IFN-producing killer dendritic cells (IKDC) and group 1 innate lymphoid cells (ILC1) are some of the recently discovered immune cells found to infiltrate tumors and to produce IFN-γ [ 15 , 16 , 17 , 18 ]. With revived scientific interest for studying immune components of tumor microenvironments, the list of IFN-γ producers is expected to be further expanded.…”

Immune Landscape in Tumor Microenvironment: Implications for Biomarker Development and Immunotherapy

“…Finally, it is important to note that, while the characterization of tumor infiltration is very informative, the TME is not only restricted to the tumor itself but also involves the surrounding tissues (which are dynamically affected by the pathological process) as documented in pancreatic cancer by TILS (tumor-infiltrating T cells) cloning [ 58 ] and in hepatocellular carcinoma (HCC) using single-cell RNA sequencing [ 59 ]. By analyzing the immune component in peritumoral hepatic tissue, hepatic lymph nodes, and ascites in the peritoneal cavity.…”