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

Elena Niccolai,Daniele Giordano,Marisa Benagiano,Fabio Cianchi,Francesca Castiglione,Francesco Novelli,Domenico Prisco,Alessandro Pini,Simona Rolla,Andrea Coratti,Antonio Taddei,Paolo Bechi,Maria Novella Ringressi,Amedeo Amedei,Daniele Bani,Lapo Bencini,Federica Ricci,Maria Antonietta Satolli,Mario Milco D'Elios

doi:10.1042/cs20150437

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.

Highlights

Pancreatic cancer is the fifth leading cause of cancer-related death in the developed world, with more than 260000 annual deaths worldwide [1] and with a dismal 5-year survival (5 %)
We evaluated the IL-22 levels secreted by the T-cell clone(s) (Tcc), and we found that the IL-22producing Tcc isolated from the tumour tissue significantly (P < 0.0001) produced higher levels of IL-22 compared with the Tcc generated from the healthy pancreas (Figure 1B)
The distribution of the two IL-22 receptors, IL-22R1 and IL-10 receptor 2 (IL-10R2), indicates that the most important target cells of IL-22 reside in the skin, digestive system, lungs, and kidney

Summary

Introduction

Pancreatic cancer is the fifth leading cause of cancer-related death in the developed world, with more than 260000 annual deaths worldwide [1] and with a dismal 5-year survival (5 %). The lethality of pancreatic cancer is due to its aggressive nature and its tendency to remain asymptomatic until the tumour reaches an advanced stage, limiting the likelihood of early diagnosis. At the time of initial presentation, most pancreatic cancers are locally advanced or metastatic and need multimodal therapy [2], the need to find factors that may facilitate earlier diagnosis and improve prognosis of this neoplasia. Pancreatic cancer originates in the ductal epithelium and evolves from a pre-malignant lesion to fully invasive cancer. The causes of pancreatic cancer remain unknown, some studies have shown that chronic inflammation is a common.

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Conclusion