Pak2 regulates myeloid-derived suppressor cell development in mice
Author
Zeng, Yi
Hahn, Seongmin
Stokes, Jessica
Hoffman, Emely A.
Schmelz, Monika
Proytcheva, Maria
Chernoff, Jonathan

Katsanis, Emmanuel

Affiliation
Univ Arizona, Dept Pediat, Steele Childrens Res CtrUniv Arizona, Ctr Canc
Univ Arizona, Dept Pathol
Univ Arizona, Dept Immunobiol
Univ Arizona, Dept Med
Issue Date
2017-10-10
Metadata
Show full item recordPublisher
AMER SOC HEMATOLOGYCitation
Pak2 regulates myeloid-derived suppressor cell development in mice 2017, 1 (22):1923 Blood AdvancesJournal
Blood AdvancesRights
© 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
2473-95292473-9537
Version
Final published versionSponsors
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 Answersae974a485f413a2113503eed53cd6c53
10.1182/bloodadvances.2017007435