A core of kinase-regulated interactomes defines the neoplastic MDSC lineage
Maria Gato-Cañas1,2, Xabier Martinez de Morentin3, Idoia Blanco-Luquin1,2
1Immunomodulation Group, Navarrabiomed-FMS, IdiSNA, Pamplona, Spain.
Abstract:
Myeloid-derived suppressor cells (MDSCs) differentiate from bone marrow precursors, expand in cancer-bearing hosts and accelerate tumor progression. MDSCs have become attractive therapeutic targets, as their elimination strongly enhances anti-neoplastic treatments. Here, immature myeloid dendritic cells (DCs), MDSCs modeling tumor-infiltrating subsets or modeling non-cancerous (NC)-MDSCs were compared by in-depth quantitative proteomics. We found that neoplastic MDSCs differentially expressed a core of kinases which controlled lineage-specific (PI3K-AKT and SRC kinases) and cancer-induced (ERK and PKC kinases) protein interaction networks (interactomes). These kinases contributed to some extent to myeloid differentiation. However, only AKT and ERK specifically drove MDSC differentiation from myeloid precursors. Interfering with AKT and ERK with selective small molecule inhibitors or shRNAs selectively hampered MDSC differentiation and viability. Thus, we provide compelling evidence that MDSCs constitute a distinct myeloid lineage distinguished by a "kinase signature" and well-defined interactomes. Our results define new opportunities for the development of anti-cancer treatments targeting these tumor-promoting immune cells.
Insights
Myeloid-derived suppressor cells (MDSCs) are key drivers of tumor progression. Targeting specific kinases like AKT and ERK selectively halts MDSC differentiation and viability, offering new anti-cancer strategies.
Area of Science:
- Immunology
- Cancer Biology
- Proteomics
Background:
- Myeloid-derived suppressor cells (MDSCs) are immune cells that promote tumor growth and progression.
- MDSCs are recognized as critical therapeutic targets for enhancing anti-cancer treatments.
Purpose of the Study:
- To compare neoplastic and non-cancerous myeloid-derived suppressor cells (MDSCs) using quantitative proteomics.
- To identify key kinases and protein interaction networks (interactomes) that define MDSCs.
- To explore the therapeutic potential of targeting identified kinases in MDSC differentiation and viability.
Main Methods:
- In-depth quantitative proteomics was employed to analyze immature myeloid dendritic cells (DCs), tumor-infiltrating MDSCs, and non-cancerous (NC)-MDSCs.
- Bioinformatic analysis was used to identify differentially expressed kinases and their associated interactomes.
- Selective small molecule inhibitors and shRNAs were utilized to interfere with specific kinase pathways (AKT and ERK).
Main Results:
- Neoplastic MDSCs exhibited differential expression of core kinases, including PI3K-AKT, SRC, ERK, and PKC.
- AKT and ERK kinases were identified as the specific drivers of MDSC differentiation from myeloid precursors.
- Inhibition of AKT and ERK pathways significantly impaired MDSC differentiation and viability.
Conclusions:
- Myeloid-derived suppressor cells (MDSCs) represent a distinct myeloid lineage characterized by a unique "kinase signature" and interactomes.
- Targeting AKT and ERK pathways offers a promising strategy for developing novel anti-cancer therapies against MDSCs.
- These findings open new avenues for therapeutic interventions aimed at modulating tumor-promoting immune cells.
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