Pak2 regulates myeloid-derived suppressor cell development in mice

Persistent Link:
http://hdl.handle.net/10150/626038
Title:
Pak2 regulates myeloid-derived suppressor cell development in mice
Author:
Zeng, Yi ( 0000-0003-1364-1854 ) ; Hahn, Seongmin; Stokes, Jessica; Hoffman, Emely A.; Schmelz, Monika; Proytcheva, Maria; Chernoff, Jonathan ( 0000-0002-4803-7836 ) ; Katsanis, Emmanuel ( 0000-0003-1466-6965 )
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
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

Full metadata record

DC FieldValue Language
dc.contributor.authorZeng, Yien
dc.contributor.authorHahn, Seongminen
dc.contributor.authorStokes, Jessicaen
dc.contributor.authorHoffman, Emely A.en
dc.contributor.authorSchmelz, Monikaen
dc.contributor.authorProytcheva, Mariaen
dc.contributor.authorChernoff, Jonathanen
dc.contributor.authorKatsanis, Emmanuelen
dc.date.accessioned2017-11-13T15:55:43Z-
dc.date.available2017-11-13T15:55:43Z-
dc.date.issued2017-10-10-
dc.identifier.citationPak2 regulates myeloid-derived suppressor cell development in mice 2017, 1 (22):1923 Blood Advancesen
dc.identifier.issn2473-9529-
dc.identifier.issn2473-9537-
dc.identifier.doi10.1182/bloodadvances.2017007435-
dc.identifier.urihttp://hdl.handle.net/10150/626038-
dc.description.abstractMyeloid-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.en
dc.description.sponsorshipNational 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 Answersen
dc.language.isoenen
dc.publisherAMER SOC HEMATOLOGYen
dc.relation.urlhttp://www.bloodadvances.org/lookup/doi/10.1182/bloodadvances.2017007435en
dc.rights© 2017 by The American Society of Hematologyen
dc.titlePak2 regulates myeloid-derived suppressor cell development in miceen
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Dept Pediat, Steele Childrens Res Ctren
dc.contributor.departmentUniv Arizona, Ctr Cancen
dc.contributor.departmentUniv Arizona, Dept Patholen
dc.contributor.departmentUniv Arizona, Dept Immunobiolen
dc.contributor.departmentUniv Arizona, Dept Meden
dc.identifier.journalBlood Advancesen
dc.description.collectioninformationThis 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.en
dc.eprint.versionFinal published versionen
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