A core of kinase-regulated interactomes defines the neoplastic MDSC lineage

Oncotarget
Maria Gato-CañasEnrique Santamaría

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.

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Citations

Sep 9, 2017·Oncotarget·Hugo ArasanzDavid Escors
Jan 10, 2018·The Journal of Immunology : Official Journal of the American Association of Immunologists·Suzanne Ostrand-Rosenberg, Catherine Fenselau
Oct 3, 2018·Signal Transduction and Targeted Therapy·David EscorsGrazyna Kochan
May 24, 2019·International Journal of Molecular Sciences·Iris C SalaroglioChiara Riganti
Sep 27, 2019·Journal of Leukocyte Biology·Arjun SukumaranJennifer Geddes-McAlister
Dec 21, 2017·Intractable & Rare Diseases Research·Xiaodan ZhengChengfang Yao
Apr 23, 2020·Frontiers in Pharmacology·Luisa Chocarro de ErausoDavid Escors
Jan 20, 2018·Nature Immunology·Filippo VegliaDmitry Gabrilovich
Aug 24, 2019·Journal of Hematology & Oncology·Xinyu TianShengjun Wang
May 4, 2016·Immunotherapy·Maria Gato-CañasDavid Escors
Jan 23, 2018·Frontiers in Immunology·Anca Dorhoi, Nelita Du Plessis
Jan 6, 2017·Cancer Immunology Research·Dmitry I Gabrilovich
Jan 19, 2021·Nature Cancer·Ting LiYouhai H Chen
Jan 9, 2021·Journal of Experimental & Clinical Cancer Research : CR·Huanhuan HuangChao Ni
Mar 13, 2019·Reports of Practical Oncology and Radiotherapy : Journal of Greatpoland Cancer Center in Poznań and Polish Society of Radiation Oncology·Marta BarradoFernando Arias
Mar 17, 2018·Current Opinion in Immunology·Evgenii TcyganovDmitry I Gabrilovich
Dec 20, 2017·Seminars in Immunology·Jie ZhouDmitry Gabrilovich
Jun 12, 2021·Frontiers in Oncology·Kenneth K W ToWilliam C S Cho

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Datasets Mentioned

BETA
PXD001103
PXD001106

Methods Mentioned

BETA
flow cytometry

Software Mentioned

Ingenuity
R scripts
STRING ( Search Tool for the Retrieval of Interacting Genes )
Ingenuity Pathway Analysis tool
Ingenuity Pathway Analysis
Ingenuity Pathway Analysis Tool ( Qiagen
STRING
SPSS
Limma Bioconductor
MaxQuant

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