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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.

Original publication

DOI

10.18632/oncotarget.4746

Type

Journal article

Journal

Oncotarget

Publication Date

29/09/2015

Volume

6

Pages

27160 - 27175

Keywords

MDSC, interactomes, kinases, proteomics, therapeutic targets, Animals, Bone Marrow Cells, Cell Differentiation, Cell Lineage, Cell Survival, Dendritic Cells, Electric Impedance, Extracellular Signal-Regulated MAP Kinases, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Inhibitory Concentration 50, Melanoma, Experimental, Mice, Mice, Inbred C57BL, Myeloid Cells, Neoplasms, Phosphatidylinositol 3-Kinases, Proteasome Endopeptidase Complex, Proteomics, Proto-Oncogene Proteins c-akt, RNA, Small Interfering, Signal Transduction