Pro‐tumour activity of interleukin‐22 in HPAFII human pancreatic cancer cells

Summary Interleukin (IL)‐22 is a cytokine involved in inflammatory and wound healing processes that is secreted primarily by T helper type 17 (Th17) cells. IL‐22 receptor (IL‐22R) expression is limited to epithelial cells of the digestive organs, respiratory tract and skin. Most tumours originating in these sites over‐express IL‐22R. Interestingly, there is an increase in Th17 frequency within the peripheral blood and tumour microenvironment of advanced cancer patients. Subsequently, IL‐17 has been shown to display both pro‐tumour and anti‐tumour functions. Because many tumours lack expression of the IL‐17 receptor, the effects of IL‐17 on tumour growth are generated by cells that surround the tumour cells. Like IL‐17, high levels of IL‐22 have been detected in tumour tissues and the peripheral blood of cancer patients; however, the direct effect of IL‐22 on tumour cells has remained largely unknown. In this report, we show that IL‐22 stimulated production of vascular endothelial growth factor (VEGF) and the anti‐apoptotic factor Bcl‐X L in IL‐22R‐positive HPAFII human pancreatic cancer cells. Additionally, IL‐22 augmented HPAFII cell production of immunosuppressive cytokines. We show further that IL‐22 activation of HPAFII cells diminished T cell production of interferon (IFN)‐γ through the action of IL‐10. Strikingly, we show for the first time that IL‐22 can fully protect cancer cells from natural killer (NK) cell‐mediated cytotoxicity by stimulating tumour production of IL‐10 and transforming growth factor (TGF)‐β1. Our data support the idea that IL‐22 may act to promote the pathogenesis of cancers rather than function in anti‐tumour immunity.