Pak2 regulates myeloid-derived suppressor cell development in mice
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 myeloi...
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AMER SOC HEMATOLOGY
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ndltd-arizona.edu-oai-arizona.openrepository.com-10150-6260382017-11-15T03:00:27Z Pak2 regulates myeloid-derived suppressor cell development in mice Zeng, Yi Hahn, Seongmin Stokes, Jessica Hoffman, Emely A. Schmelz, Monika Proytcheva, Maria Chernoff, Jonathan Katsanis, Emmanuel Univ Arizona, Dept Pediat, Steele Childrens Res Ctr Univ Arizona, Ctr Canc Univ Arizona, Dept Pathol Univ Arizona, Dept Immunobiol Univ Arizona, Dept Med 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. 2017-10-10 Article Pak2 regulates myeloid-derived suppressor cell development in mice 2017, 1 (22):1923 Blood Advances 2473-9529 2473-9537 10.1182/bloodadvances.2017007435 http://hdl.handle.net/10150/626038 http://arizona.openrepository.com/arizona/handle/10150/626038 Blood Advances en http://www.bloodadvances.org/lookup/doi/10.1182/bloodadvances.2017007435 © 2017 by The American Society of Hematology AMER SOC HEMATOLOGY |
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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. |
author2 |
Univ Arizona, Dept Pediat, Steele Childrens Res Ctr |
author_facet |
Univ Arizona, Dept Pediat, Steele Childrens Res Ctr Zeng, Yi Hahn, Seongmin Stokes, Jessica Hoffman, Emely A. Schmelz, Monika Proytcheva, Maria Chernoff, Jonathan Katsanis, Emmanuel |
author |
Zeng, Yi Hahn, Seongmin Stokes, Jessica Hoffman, Emely A. Schmelz, Monika Proytcheva, Maria Chernoff, Jonathan Katsanis, Emmanuel |
spellingShingle |
Zeng, Yi Hahn, Seongmin Stokes, Jessica Hoffman, Emely A. Schmelz, Monika Proytcheva, Maria Chernoff, Jonathan Katsanis, Emmanuel Pak2 regulates myeloid-derived suppressor cell development in mice |
author_sort |
Zeng, Yi |
title |
Pak2 regulates myeloid-derived suppressor cell development in mice |
title_short |
Pak2 regulates myeloid-derived suppressor cell development in mice |
title_full |
Pak2 regulates myeloid-derived suppressor cell development in mice |
title_fullStr |
Pak2 regulates myeloid-derived suppressor cell development in mice |
title_full_unstemmed |
Pak2 regulates myeloid-derived suppressor cell development in mice |
title_sort |
pak2 regulates myeloid-derived suppressor cell development in mice |
publisher |
AMER SOC HEMATOLOGY |
publishDate |
2017 |
url |
http://hdl.handle.net/10150/626038 http://arizona.openrepository.com/arizona/handle/10150/626038 |
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