Pak2 regulates myeloid-derived suppressor cell development in mice

Yi Zeng, Seongmin Hahn, Jessica Stokes, Emely A. Hoffman, Monika Schmelz, Maria Proytcheva, Jonathan Chernoff, Emmanuel Katsanis

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Myeloid-derived suppressor cells (MDSCs) are CD11b1Gr11 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 CD11bhighGr1high cells in mice. In this study, we confirmed that Pak2-KO CD11bhighGr1high 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 CD41 T cells that produced more interferon g, tumor necrosis factor a, 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.

Original languageEnglish (US)
Pages (from-to)1923-1933
Number of pages11
JournalBlood Advances
Volume1
Issue number22
DOIs
StatePublished - Oct 10 2017

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Hematopoietic Stem Cells
Granulocyte-Macrophage Colony-Stimulating Factor
p21-Activated Kinases
T-Lymphocytes
Cell Proliferation
Tumor Escape
Myeloid-Derived Suppressor Cells
Interferons
Immunity
Carcinogenesis
Transcription Factors
Down-Regulation
Tumor Necrosis Factor-alpha
Apoptosis
Phenotype
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Hematology

Cite this

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.

In: Blood Advances, Vol. 1, No. 22, 10.10.2017, p. 1923-1933.

Research output: Contribution to journalArticle

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. In: Blood Advances. 2017 ; Vol. 1, No. 22. pp. 1923-1933.
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