Journal
ONCOTARGET
Volume 6, Issue 29, Pages 27160-27175Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.4746
Keywords
MDSC; proteomics; interactomes; kinases; therapeutic targets
Categories
Funding
- Miguel Servet Fellowship [CP12/03114]
- FIS project grant from Instituto de Salud Carlos III, Spain [PI14/00579]
- Refbio transpyrenaic collaborative project grants (NTBM)
- Sandra Ibarra Foundation grant
- Gobierno de Navarra Grant [BMED 033-2014]
- Gobierno Vasco BioEf project grant [BIO13/CI/014]
- BD Bioscience Spring Immunology Award
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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.
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