uPAR(+) extracellular vesicles: a robust biomarker of resistance to checkpoint inhibitor immunotherapy in metastatic melanoma patients

BACKGROUND: Emerging evidence has highlighted the importance of extracellular vesicle (EV)-based biomarkers of resistance to immunotherapy with checkpoint inhibitors in metastatic melanoma. Considering the tumor-promoting implications of urokinase-type plasminogen activator receptor (uPAR) signaling, this study aimed to assess uPAR expression in the plasma-derived EVs of patients with metastatic melanoma to determine its potential correlation with clinical outcomes. METHODS: Blood samples from 71 patients with metastatic melanoma were collected before initiating immunotherapy. Tumor-derived and immune cell-derived EVs were isolated and analyzed to assess the relative percentage of uPAR(+) EVs. The associations between uPAR and clinical outcomes, sex, BRAF status, baseline lactate dehydrogenase levels and number of metastatic sites were assessed. RESULTS: Responders had a significantly lower percentage of tumor-derived, dendritic cell (DC)-derived and CD8(+) T cell-derived uPAR +EVs at baseline than non-responders. The Kaplan-Meier survival curves for the uPAR(+)EV quartiles indicated that higher levels of melanoma-derived uPAR(+) EVs were strongly correlated with poorer progression-free survival (p<0.0001) and overall survival (p<0.0001). We also found a statistically significant correlation between lower levels of uPAR(+) EVs from both CD8(+) T cells and DCs and better survival. CONCLUSIONS: Our results indicate that higher levels of tumor-derived, DC-derived and CD8(+) T cell-derived uPAR(+) EVs in non-responders may represent a new biomarker of innate resistance to immunotherapy with checkpoint inhibitors. Moreover, uPAR(+) EVs represent a new potential target for future therapeutic approaches.