Interleukin-15 is a major regulator of the cell-microenvironment interactions in human renal cancer.

Primary human epithelial renal cells of normal (HRE), paratumoral (pTEC) and tumoral (RCC) origin display important differences, concerning the expression and biological effects of the IL-15/IL-15R system that deeply influences the evolution of the tumour microenvironment. A major distinguishing feature is represented in RCC and pTEC by the loss of the γc chain leading to the assembly of a IL-15Rαβ heterodimer that in response to physiologic concentrations of IL-15 initiates the process of their epithelial–mesenchymal transition (EMT). In contrast, this treatment in HRE cells, which display the IL-15Rαβγc heterotrimer, causes opposite effects inhibiting their drift towards EMT. Thus, IL-15 at physiologic concentrations displays novel functions acting as a major regulator of renal epithelial homeostasis. As second distinguishing feature, RCC and pTEC but not HRE cells express a trans-membrane-bound IL-15 (tmb-IL-15) able to deliver a reverse signal in response to the soluble IL-15Rα chain inducing their EMT. In conclusion, comparison of primary normal (HRE) to primary pathological cells (pTEC and RCC) highlights two major issues: (1) IL-15 is a major regulator of epithelial homeostasis; (2) “apparently normal” pTEC cells, could contribute to organize a generalized “pre-neoplastic” environment committed to favour tumour progression.