High Blood Concentration of Leukocyte-Derived Extracellular Vesicles Is Predictive of Favorable Clinical Outcomes in Patients with Pancreatic Cancer: Results from a Multicenter Prospective Study

Pancreatic cancer (PC) is one of the leading causes of cancer-related death worldwide.Identification of novel tumor biomarkers is highly advocated in PC to optimize personalized treatmentalgorithms. Blood-circulating extracellular vesicles hold promise for liquid biopsy application incancer. We used an optimized flow cytometry protocol to study leukocyte-derived EVs (CD45+) andPD-L1+ EVs in blood from 56 pancreatic cancer patients and 48 healthy controls (HCs). Our resultsshow that PC patients presented higher blood levels of total EVs (p= 0.0003), leukocyte-derivedEVs (LEVs) (p= 0.001) and PD-L1+ EVs (p= 0.01), as compared with HCs. Interestingly, a bloodconcentration of LEVs at baseline was independently associated with improved overall survivalin patients with borderline resectable or primary unresectable PC (HR = 0.17; 95% CI 0.04–0.79;p= 0.02). Additionally, increased blood-based LEVs were independently correlated with prolongedprogression-free survival (HR = 0.10; 95% CI 0.01–0.82;p= 0.03) and significantly associated withhigher disease control rate (p= 0.02) in patients with advanced PC receiving standard chemotherapy.Notably, a strong correlation between a decrease in blood LEVs concentration during chemotherapy and disease control was observed (p= 0.005). These intriguing findings point to the potential of LEVsas novel blood-based EV biomarkers for improved personalized medicine in patients affected by PC.