BRIEF RESEARCH REPORT article
Front. Immunol.
Sec. Immunological Tolerance and Regulation
This article is part of the Research TopicImmunomics: Dynamics of Circulating Vesicles in the Immune Regulatory NetworksView all articles
Pazopanib-associated remodeling of platelet-immune cell crosstalk and immune suppressive platelet-derived extracellular vesicles in metastatic RCC
Provisionally accepted
Gianpiero Lupoli*
Jeannette Salsetta
Stefano BergaminiAlessandro Mereu
Agata Cova
Elisa D'Angelo
Eriomina Shahaj
Elisabetta Vergani
Licia Rivoltini
Elena Verzoni
Veronica Huber*- National Cancer Institute Foundation (IRCCS), Milan, Italy
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Background: 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. Methods: 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. Results: Pazopanib induced temporally structured EV compartment alterations. After 3 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 6 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. Conclusions: Despite the small sample size and absence of functional experiments, our results suggest that Pazopanib promotes cytotoxic immune programs but, by 6 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.
Keywords: Antiangiogenics, TKI, rcc, immune suppression, extracellular vesicles, platelets
Received: 31 Aug 2025; Accepted: 12 Dec 2025.
Copyright: © 2025 Lupoli, Salsetta, Bergamini, Mereu, Cova, D'Angelo, Shahaj, Vergani, Rivoltini, Verzoni and Huber. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Gianpiero Lupoli
Veronica Huber
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