Abstract
Interleukin-15 (IL-15) is expressed in various cancers, including melanoma, where it exists in distinct membrane-associated isoforms. Primary melanoma cells predominantly express the non-cleavable transmembrane form (tmbIL-15), while metastatic cells also express a cleavable membrane-bound form (mbIL-15) complexed with IL-15Rα. As tmbIL-15 is capable of reverse signaling upon IL-15Rα engagement, we investigated how this signaling axis modulates melanoma cell behavior across tumor stages. Transcriptomic analysis of melanoma patients revealed that high IL-15 expression correlates with immune activation, inflammation and epithelial-to-mesenchymal transition (EMT), along with coordinated upregulation of IL-15 receptor subunits. Proteomic profiling of melanoma cell lines stimulated with soluble IL-15Rα (sIL-15Rα) uncovered distinct, stage-specific responses. Although several proteins were commonly deregulated across cell lines, most showed opposite regulation in primary versus metastatic models, indicating that tmbIL-15 reverse signaling triggers context-dependent programs influenced by tumor progression. A stringent cross-comparison identified five proteins (PSAP, MARCKS, eEF1A1, DDX39B, and RACK1) as consistently and differentially regulated across tumor stages. Further comparison with published NK cell co-culture and EMT cytokine stimulation datasets revealed a subset of shared effectors, notably PSAP, TPM3 isoform 2 and MARCKS, suggesting that IL-15Rα-induced tmbIL-15 signaling is part of the immune editing phenomenon eliciting pro-tumoral activities complementary to the EMT process. Among these, PSAP emerged as the most robustly and consistently modulated effector, upregulated in primary melanoma cells and downregulated in metastatic ones upon sIL-15Rα stimulation. Its expression correlated positively with CD8+ T cell infiltration and negatively with NK cell infiltration, with distinct transcriptomic programs associated with high PSAP expression in primary versus metastatic settings. Altogether, these findings identify PSAP as a stage-specific mediator of tmbIL-15 reverse signaling in melanoma, integrating immune and EMT-related cues with potential implications for tumor progression and microenvironmental remodeling.