Pak2 regulates myeloid-derived suppressor cell development in mice

• Main Authors: Zeng, Yi, Hahn, Seongmin, Stokes, Jessica, Hoffman, Emely A., Schmelz, Monika, Proytcheva, Maria, Chernoff, Jonathan, Katsanis, Emmanuel
• Other Authors: Univ Arizona, Dept Pediat, Steele Childrens Res Ctr
• Language: en
• Published: AMER SOC HEMATOLOGY 2017
• Online Access: http://hdl.handle.net/10150/626038; http://arizona.openrepository.com/arizona/handle/10150/626038

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.