Antiangiogenics promote immune activation by reducing myeloid-derived suppressor cells (MDSCs) and enhancing natural killer (NK) and T cell functions in metastatic RCC patients. However, these effects are transient, leading to compensatory immunosuppression. Platelets (PLT) and their extracellular vesicles (PLT-EVs) modulate immune and angiogenic pathways, suggesting a role in immune reprogramming during therapy.
Circulating EVs were longitudinally profiled in metastatic RCC patients (n=8) undergoing Pazopanib therapy. EVs, isolated by differential ultracentrifugation from baseline, 3- and 6-month plasma samples, were characterized by bead-based multiplex assay and nanoparticle tracking analysis. Results were correlated with blood counts, RNA-seq and flow cytometry immune profiles.
Pazopanib induced temporally structured EV compartment alterations. After three months, EVs were enriched in immune markers (CD8, CD56, CD19, CD1c, HLA-DR), consistent with immune activation, whereas PLT-derived markers (CD41b, CD42a, CD29) were diminished. By six months, PLT-EV markers recovered, with CD62P+ and CD29+ EVs co-expressing immunoregulatory and angiogenic molecules (CD209, CD105). PLT-EV abundance correlated with the expansion of regulatory T cells (Tregs), PD-L1+ monocytes and MDSCs, together with suppression of NK cells. PLT activation and PDGF signaling pathways decreased in PBMC from patients with clinical benefit.
Despite the small sample size and absence of functional experiments, our results suggest that Pazopanib promotes cytotoxic immune programs but, by six months, reprograms PLT-EVs towards different adhesion characteristics contributing to Treg and MDSC expansion while suppressing NK activity. PLT-EVs may influence the balance between immune activation and suppression during anti-angiogenic therapy, suggesting PLT-EVs as biomarkers and therapeutic targets in mRCC.
Frontiers in immunology. 2026 Jan 07*** epublish ***
Gianpiero Lupoli, Stefano Bergamini, Jeannette Salsetta, Alessandro Mereu, Agata Cova, Elisa D'Angelo, Eriomina Shahaj, Elisabetta Vergani, Martina Stroscia, Emma Di Carlo, Licia Rivoltini, Elena Verzoni, Veronica Huber
Translational Immunology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Department of Medicine and Sciences of Aging, PhD Program in "Molecular Oncology and Tumor Immunology", "G. d'Annunzio University" of Chieti-Pescara, Chieti, Italy., Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.