Protein content of extracellular vesicles from patients with advanced melanoma changes upon progression to anti-PD1 therapy

This study investigates the role of extracellular vesicles (EVs) in predicting melanoma patients' responses to anti-PD1 immunotherapy. Nine patients with advanced melanoma provided blood samples at three stages: before treatment, before the second dose, and either at disease progression or nine months later. EVs were isolated from serum and analyzed using mass-spectrometry proteomics, followed by network and enrichment analyses. Six out of nine patients progressed despite treatment. Before therapy, responders exhibited higher levels of adaptive immune and cell adhesion proteins, while proteins related to UV radiation response were deplected. An eight-protein signature and cellular adhesion markers correlated with longer progression-free survival. After treatment, non-responders had EV proteins enriched in proteasome activity and metabolic pathways, especially glycolysis. Finally, dynamic changes in EV protein over time showed decreased coagulation proteins, along with an increase in MHC proteins in patients with progressive disease. Overall, EV protein profiles differed between responders and non-responders both before and during therapy. These findings suggest that EVs could provide predictive biomarkers and insights into resistance mechanisms, potentially guiding more effective melanoma treatment strategies.