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    Pak2 regulates myeloid-derived suppressor cell development in mice

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    Author
    Zeng, Yi cc
    Hahn, Seongmin
    Stokes, Jessica
    Hoffman, Emely A.
    Schmelz, Monika
    Proytcheva, Maria
    Chernoff, Jonathan cc
    Katsanis, Emmanuel cc
    Affiliation
    Univ Arizona, Dept Pediat, Steele Childrens Res Ctr
    Univ Arizona, Ctr Canc
    Univ Arizona, Dept Pathol
    Univ Arizona, Dept Immunobiol
    Univ Arizona, Dept Med
    Issue Date
    2017-10-10
    
    Metadata
    Show full item record
    Publisher
    AMER SOC HEMATOLOGY
    Citation
    Pak2 regulates myeloid-derived suppressor cell development in mice 2017, 1 (22):1923 Blood Advances
    Journal
    Blood Advances
    Rights
    © 2017 by The American Society of Hematology.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Myeloid-derived suppressor cells (MDSCs) are CD11b(+)Gr1(+) cells that induce T-cell hyporesponsiveness, thus impairing antitumor immunity. We have previously reported that disruption of Pak2, a member of the p21-activated kinases (Paks), in hematopoietic stem/progenitor cells (HSPCs) induces myeloid lineage skewing and expansion of CD11b(high)Gr1(high) cells in mice. In this study, we confirmed that Pak2-KO CD11b(high)Gr1(high) cells suppressed T-cell proliferation, consistent with an MDSC phenotype. Loss of Pak2 function in HSPCs led to (1) increased hematopoietic progenitor cell sensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, (2) increased MDSC proliferation, (3) decreased MDSC sensitivity to both intrinsic and Fas-Fas ligand-mediated apoptosis, and (4) promotion of MDSCs by Pak2-deficient CD4(+) T cells that produced more interferon gamma, tumor necrosis factor alpha, and GM-CSF. Pak2 disruption activated STAT5 while downregulating the expression of IRF8, a well-described myeloid transcription factor. Together, our data reveal a previously unrecognized role of Pak2 in regulating MDSC development via both cell-intrinsic and extrinsic mechanisms. Our findings have potential translational implications, as the efficacy of targeting Paks in cancer therapeutics may be undermined by tumor escape from immune control and/or acceleration of tumorigenesis through MDSC expansion.
    ISSN
    2473-9529
    2473-9537
    DOI
    10.1182/bloodadvances.2017007435
    Version
    Final published version
    Sponsors
    National Institutes of Health, National Cancer Institute [R01 CA104926, R01 CA142928]; Hyundai Hope on Wheels; Tee Up for Tots; Angel Charity for Children; People Acting Now Discover Answers
    Additional Links
    http://www.bloodadvances.org/lookup/doi/10.1182/bloodadvances.2017007435
    ae974a485f413a2113503eed53cd6c53
    10.1182/bloodadvances.2017007435
    Scopus Count
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    UA Faculty Publications

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