IL-15 is produced by a subset of human melanomas, and is involved in the regulation of markers of melanoma progression through juxtacrine loops

IL-15 is a novel cytokine active through the IL-2R beta gamma. Since several human melanoma cell lines display functional IL-2Rs, we studied the IL-15/melanoma cells interactions. Ten out of 17 melanoma cell lines express the IL-15 transcript and four of them express levels of IL-15 mRNA similar to those detected in control activated monocytes, Nine out of ten cell lines also express two transcripts for the IL-15R alpha originated by the alternative splicing of exon'3'. Two melanoma cell lines, MELP and MELREO, derived from patients with rapidly progressive primary melanomas, co-express the two IL-15 transcripts, originated by alternative splicing of exon 'A'. Intracellular II-15 protein was only detected in these two cells lines and it is mainly retained in the Endoplasmic Reticulum (ER), However, a small amount of IL-15 is also found in the GoIgi apparatus and in the early endosomes, suggesting production and intercellular trafficking of endogenous IL-15 protein. Nevertheless, no biologically active IL-15 could be detected in the supernatant of all melanoma cells. The anti IL-15 blocking mAb M111 causes the up regulation of;HLA Class I in dense MELP and MELREO cultures, These data suggest that IL-15 is probably active through juxtacrine loops negatively controlling KLA Class I molecules expression. These data offer, for the first time, a likely explanation to the controversal issue of IL-15 secretion and constitute a natural model for understanding IL-15 routing. Moreover, me identify a subset of melanoma cells producing IL-15, possibly involved in tumor escape mechanisms.