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

SIMPLE SUMMARY: Blood-circulating extracellular vesicles (EVs) are emerging as key players to develop novel liquid biopsy-based approaches in cancer, including pancreatic cancer. In this study, we aimed to explore the prognostic and predictive value of blood-circulating extracellular vesicles released by immune cells in patients with pancreatic cancer. A recently patented flow cytometry protocol was applied for the identification and phenotypical characterization of blood-circulating EVs in a cohort of 56 patients with pancreatic cancer (PC) and in a group of 48 healthy controls. We observed an increased blood concentration of leukocyte-derived EVs (CD45+) and PD-L1+ EVs in patients with PC as compared to healthy controls. Intriguingly, a high blood concentration of leukocyte-derived EVs identified PC patients with a good prognosis and improved clinical outcomes. This study revealed the promising role of EVs released by immune cells as a source of candidate biomarkers in patients with pancreatic cancer. ABSTRACT: 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 treatment algorithms. Blood-circulating extracellular vesicles hold promise for liquid biopsy application in cancer. We used an optimized flow cytometry protocol to study leukocyte-derived EVs (CD45+) and PD-L1+ EVs in blood from 56 pancreatic cancer patients and 48 healthy controls (HCs). Our results show that PC patients presented higher blood levels of total EVs (p = 0.0003), leukocyte-derived EVs (LEVs) (p = 0.001) and PD-L1+ EVs (p = 0.01), as compared with HCs. Interestingly, a blood concentration of LEVs at baseline was independently associated with improved overall survival in 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 prolonged progression-free survival (HR = 0.10; 95% CI 0.01–0.82; p = 0.03) and significantly associated with higher 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 LEVs as novel blood-based EV biomarkers for improved personalized medicine in patients affected by PC.