Generation of Myeloid-Derived Suppressor Cells Mediated by MicroRNA-125a-5p in Melanoma
Samantha Lasser1,2,3,4, Feyza Gul Ozbay Kurt1,2,3,4, Lennart Fritz1,2,3,4
1Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, 68167 Mannheim, Germany.
Abstract:
The ability of tumor-derived extracellular vesicles (EVs) to modulate the function of myeloid cells is widely recognized. Hence, a comprehensive understanding of the distinct components associated with EVs and the signals that they deliver to myeloid cells could provide potential approaches to impede the immunosuppression by myeloid-derived suppressor cells (MDSCs). We investigated melanoma EV-associated microRNAs (miRs) using the RET transgenic melanoma mouse model and simulated their transfer to normal myeloid cells by transfecting immature mouse myeloid cells and human monocytes. We observed elevated levels of miR-125a-5p, -125b-5p, and let-7e-5p in mouse melanoma-infiltrating MDSCs. In addition, miR-125a-5p levels in the tumor microenvironment correlated with mouse melanoma progression. The delivery of miR-125a-5p, alone or in combination with let-7e-5p and miR-99b-5p from the same genomic cluster, to normal myeloid cells resulted in their conversion to MDSC-like cells. Our findings indicate that miR-125a-5p could modulate myeloid cell activation in the melanoma microenvironment via a NF-κB-dependent mechanism.
Insights
Tumor-derived extracellular vesicles (EVs) carry microRNAs that can transform normal myeloid cells into immunosuppressive myeloid-derived suppressor cells (MDSCs). miR-125a-5p promotes melanoma progression by modulating myeloid cell activation.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Tumor-derived extracellular vesicles (EVs) influence myeloid cell function.
- Understanding EV components is key to targeting immunosuppression by myeloid-derived suppressor cells (MDSCs).
Purpose of the Study:
- Investigate melanoma EV-associated microRNAs (miRs).
- Determine the role of specific miRs in modulating myeloid cell function towards an MDSC phenotype.
- Explore the mechanism of miR-mediated myeloid cell modulation in melanoma.
Main Methods:
- Utilized a RET transgenic melanoma mouse model.
- Analyzed microRNA content of melanoma-infiltrating MDSCs.
- Simulated EV-mediated miR transfer by transfecting normal myeloid cells and human monocytes with specific miRs.
- Assessed changes in myeloid cell phenotype and activation pathways (e.g., NF-κB).
Main Results:
- Elevated levels of miR-125a-5p, miR-125b-5p, and let-7e-5p were found in mouse melanoma-infiltrating MDSCs.
- miR-125a-5p levels correlated with melanoma progression in mice.
- Delivery of miR-125a-5p, alone or with let-7e-5p and miR-99b-5p, induced conversion of normal myeloid cells into MDSC-like cells.
- miR-125a-5p modulated myeloid cell activation via a NF-κB-dependent pathway.
Conclusions:
- Specific microRNAs, notably miR-125a-5p, are key mediators transferred by melanoma EVs.
- These miRs can reprogram myeloid cells into immunosuppressive MDSCs, contributing to the tumor microenvironment.
- Targeting miR-125a-5p presents a potential therapeutic strategy to overcome melanoma-induced immunosuppression.
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