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Bone marrow-derived extracellular vesicles from multiple myeloma patients promote adaptive immune dysfunction via
Debora Soncini1, Danilo Marimpietri2, Francesco Ladisa3
1Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genova, Italy.
Introduction:
Extracellular vesicles (EVs) are critical mediators of intercellular communication and contribute to cancer progression and immune regulation.
Methods:
We characterized EVs isolated from bone marrow (BM) plasma harvested from healthy donors and patients affected by Multiple Myeloma (MM) by Nano Tracking Analysis and by flow cytometry.
Results:
EVs from MM patients were significantly more abundant and enriched in CD138, supporting their partial origin from malignant plasma cells, with additional input from BM resident cells, including monocytes and NK cells. Phenotypic profiling revealed increased expression of immune checkpoint molecules HLA-G, PD-1, and PD-L1 on MM-derived EVs compared to healthy controls. Functionally, MM-EVs suppressed Staphylococcal enterotoxin B (SEB)-induced T cell activation, as evidenced by reduced IFN-γ production and CD4+ T cell proliferation. Such effects were partially reversed by HLA-G blockade. Moreover, MM-derived EVs modulated cytokine secretion profiles suppressing IL-2, IFN-α, TNF-α, and IL-6, and enhancing GM-CSF, with some changes attributed to HLA-G and PD-L1 activity. Transcriptomic analysis showed higher HLA-G expression in patients with gain of chromosome 1q, suggesting a link between high-risk cytogenetics and EV-driven immune suppression. While clinical correlations were not observed, likely due to limited sample size, these findings underscore the immunosuppressive role of MM-derived EVs.
Discussion:
HLA-G+, PD-1+, and PD-L1+ EVs contribute to immune dysfunction in MM and represent promising targets to restore anti-tumor immunity.
Insights
Extracellular vesicles (EVs) from Multiple Myeloma (MM) patients are more abundant and express immune checkpoint molecules, suppressing T cell responses. These MM-derived EVs, enriched in HLA-G, PD-1, and PD-L1, highlight potential therapeutic targets for restoring anti-tumor immunity.
Area of Science:
- Immunology
- Cancer Biology
- Cell Biology
Background:
- Extracellular vesicles (EVs) mediate intercellular communication and influence cancer progression and immune regulation.
- Multiple Myeloma (MM) is a hematologic malignancy characterized by uncontrolled plasma cell proliferation.
Purpose of the Study:
- To characterize EVs from MM patients and healthy donors.
- To investigate the functional role of MM-derived EVs in T cell activation and immune modulation.
- To explore the potential of targeting MM-EVs for immunotherapy.
Main Methods:
- Isolation and characterization of EVs from bone marrow plasma of MM patients and healthy donors using Nano Tracking Analysis and flow cytometry.
- Phenotypic profiling of EVs for immune checkpoint molecules (HLA-G, PD-1, PD-L1).
- Functional assays assessing T cell activation (IFN-γ production, proliferation) and cytokine secretion profiles.
- Transcriptomic analysis to correlate EV expression with cytogenetics.
Main Results:
- MM-derived EVs were more abundant and enriched in CD138 compared to controls.
- Increased expression of HLA-G, PD-1, and PD-L1 was observed on MM-EVs.
- MM-EVs suppressed T cell activation and modulated cytokine secretion, with partial reversal by HLA-G blockade.
- Higher HLA-G expression on EVs correlated with high-risk cytogenetics (gain of chromosome 1q).
Conclusions:
- MM-derived EVs contribute to immune dysfunction through immunosuppressive mechanisms.
- HLA-G+, PD-1+, and PD-L1+ EVs are key players in MM-induced immune suppression.
- Targeting these MM-EVs offers a promising strategy for restoring anti-tumor immunity in MM patients.
