Failure to Upregulate IL-2/IL-15 in Tumour Bearing Liver May Reflect Defective Effector Mechanisms

We have previously demonstrated a significant antitumour-Th1 response, evidenced by upregulation of IFN-γ levels, but a failure to upregulate IL-2 production in tumour-bearing liver, which may reflect a defect in the cytotoxic T-cell response, thus promoting tumour tolerance. IL-15 shares many biological properties with IL-2 and also plays a critical role in the development of NK/NKT cells – principal mediators of innate anti-tumour immunity. The relative deficiency of IL-2 in tumour-bearing liver may be balanced by an increase in IL-15 levels. The aim of this study was to localise and quantify IL-15 expression and to enumerate IL-15 responsive lymphocyte populations in normal and tumour-bearing liver. Normal (n=11) and tumour-bearing (n=12) liver, was snap frozen, powdered, protein was extracted and IL-15 levels were quantified using a modified ELISA. IL-15 was localised using immunohistochemistry. CD8⁺cytotoxic T-lymphocytes and NKT-cells were quantified in hepatic tissue using flow cytometry. IL-15 protein was detected in normal liver at a median concentration of 0.349ng/100mg protein. There was a significant reduction in IL-15 levels in tumour bearing liver (0.22ng/100mg protein, p=0.01). IL-15 was localised to both infiltrating monocytes within portal tracts and to perisinusoidal tissue. Surprisingly, there was no increase in CD8⁺ T-cells or NKT-cells in tumour-bearing compared to normal liver. These results suggest that, while there is a significant anti-tumour immune response in tumour-bearing liver, the lack of a significant increase in IL-2 and the down regulation of IL-15 levels, may reflect a defect in both cytotoxic T-cell and innate immune responses, thus promoting tumour progression.