Journal Article

Pazopanib-associated remodeling of platelet-immune cell crosstalk and immune suppressive platelet-derived extracellular vesicles in metastatic RCC

Vergani, Elisabetta, Di Carlo, Emma, Lupoli, Gianpiero, Stroscia, Martina, Shahaj, Eriomina, D’Angelo, Elisa, Mereu, Alessandro, Huber, Veronica, Verzoni, Elena, Rivoltini, Licia, Bergamini, Stefano, Cova, Agata, Salsetta, Jeannette

2026

Overview

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.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Aged / Angiogenesis / Angiogenesis Inhibitors - pharmacology / Angiogenesis Inhibitors - therapeutic use / antiangiogenics / Biomarkers / Blood platelets / Blood Platelets - drug effects / Blood Platelets - immunology / Blood Platelets - metabolism / Carcinoma, Renal Cell - blood / Carcinoma, Renal Cell - drug therapy / Carcinoma, Renal Cell - immunology / Carcinoma, Renal Cell - pathology / CD105 antigen / CD19 antigen / CD1c antigen / CD29 antigen / CD56 antigen / CD8 antigen / Cell activation / Cell Communication - drug effects / Cell Communication - immunology / Cytotoxicity / Extracellular vesicles / Extracellular Vesicles - drug effects / Extracellular Vesicles - immunology / Extracellular Vesicles - metabolism / Female / Flow cytometry / Genes / Humans / Immune response / immune suppression / Immunoregulation / Immunosuppression / Indazoles / Kidney cancer / Kidney Neoplasms - drug therapy / Kidney Neoplasms - immunology / Kidney Neoplasms - pathology / Killer Cells, Natural - immunology / Kinases / Lymphocytes T / Male / Metastases / Metastasis / Middle Aged / Monocytes / Myeloid-Derived Suppressor Cells - immunology / Nanoparticles / Natural killer cells / PD-L1 protein / Peripheral blood mononuclear cells / Plasma / Platelet-derived growth factor / Platelets / Proteins / Pyrimidines - pharmacology / Pyrimidines - therapeutic use / RCC / Software / Sulfonamides - pharmacology / Sulfonamides - therapeutic use / Suppressor cells / Therapeutic targets / TKI / Ultracentrifugation