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Platelet-Derived Extracellular Vesicle Functionalization of Ti Implants
Published on: August 5, 2021
Pazopanib-associated remodeling of platelet-immune cell crosstalk and immune suppressive platelet-derived
Gianpiero Lupoli1, Stefano Bergamini1,2, Jeannette Salsetta1
1Translational Immunology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
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 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.
Conclusions:
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.
Insights
Antiangiogenic therapy in metastatic RCC initially boosts immune cells but later promotes immunosuppression via platelet extracellular vesicles (PLT-EVs). These PLT-EVs may become therapeutic targets to rebalance immune responses.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Antiangiogenics in metastatic renal cell carcinoma (mRCC) initially enhance immune cells like NK and T cells by reducing myeloid-derived suppressor cells (MDSCs).
- However, these immune effects are transient, leading to compensatory immunosuppression during therapy.
- Platelets (PLTs) and their extracellular vesicles (PLT-EVs) are implicated in modulating immune and angiogenic pathways, potentially influencing therapeutic outcomes.
Purpose of the Study:
- To investigate the longitudinal changes in extracellular vesicles (EVs) during Pazopanib therapy in metastatic RCC patients.
- To correlate EV alterations with immune cell profiles and clinical outcomes.
- To explore the role of PLT-EVs in immune reprogramming during anti-angiogenic treatment.
Main Methods:
- Longitudinal profiling of circulating EVs from plasma of 8 metastatic RCC patients undergoing Pazopanib therapy at baseline, 3, and 6 months.
- EV isolation via differential ultracentrifugation, followed by characterization using bead-based multiplex assay and nanoparticle tracking analysis.
- Correlation of EV data with blood counts, RNA-sequencing, and flow cytometry immune profiles.
Main Results:
- Pazopanib treatment induced significant alterations in the EV compartment over time.
- At 3 months, EVs showed increased immune markers (e.g., CD8, CD56) and decreased PLT markers, indicating immune activation.
- By 6 months, PLT-EV markers recovered, co-expressing immunoregulatory and angiogenic molecules, correlating with increased regulatory T cells (Tregs), PD-L1+ monocytes, and MDSCs, and suppressed NK cell activity.
Conclusions:
- Pazopanib initially promotes cytotoxic immune responses but subsequently reprograms PLT-EVs by 6 months.
- Reprogrammed PLT-EVs contribute to the expansion of Tregs and MDSCs while suppressing NK cell activity.
- PLT-EVs may represent key modulators of the immune balance during anti-angiogenic therapy, serving as potential biomarkers and therapeutic targets in mRCC.
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