The Role of the IL-22/IL-22R1 Axis in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer with poor prognosis despite extensive efforts. JAK-STAT3 signaling plays a significant role in the development and progression of pancreatic cancer. IL-22 is a cytokine, which belongs to the IL-10 family, acts via activation of Jak/Stat3-dependent signaling cascades and is a well-described growth factor for epithelial cells.

To study the role of IL-22 in the tumor microenvironment of PDAC patients, focusing on the reciprocal interactions between IL-22-producing lymphocytes and PDAC cells we analyzed the following parameters: the expression of IL-22RA1 chain on both primary tumor cells isolated from ascites of PDAC patients and various PDAC cell lines; the pro-proliferative effect of IL-22 on these various PDCA cells in-vitro; the capacity of ascites-derived supernatants from metastatic PDAC patients to polarize naïve T cells, in vitro, towards the Th22 phenotype; and detection by intracellular staining the percentage of IL-22 secreting lymphocytes in the ascites of metastatic PDAC patients.

We found high expression of IL-22RA1 on all the primary PDAC cells and cell lines tested coupled with a significant increase in their proliferation after the addition of IL-22 to the culture medium. Moreover, isolated mononuclear cells from PDAC patients` ascites showed higher percentage of IL-22+ lymphocytes, and importantly factors found in PDAC ascites induced significant increase on the polarization of naïve T cells into Th22 cells.

In summary, we show that IL-22 has a positive effect on the growth of PDAC that uniformly express the IL-22RA1, while reciprocally the PDAC environment contains factors that can potentially instruct tissue infiltrating lymphocytes to produce the pro-proliferative and immunosuppressive cytokine IL-22 to create a positive feedback loop.