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 uPAREV 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.