Pak2 regulates myeloid-derived suppressor cell development in mice

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

doi:10.1182/bloodadvances.2017007435

Cited by 15 publications

(9 citation statements)

References 57 publications

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“…To determine absolute cell numbers in blood, white blood cell counts were determined using a HemaVet 950 (Drew Scientific, Miami Lakes, FL, USA). 40 Plasma and DC stimulation BALB/c mice received BEN or CY on day −2, TBI on day −1, and were sacrificed on day 0. Blood was collected by cardiac puncture for plasma isolation and splenic dendritic cells (DCs) were isolated using a Pan DC Isolation Kit (Miltenyi Biotec; 130-100-875).…”

Section: Flow Cytometrymentioning

confidence: 99%

Bendamustine with total body irradiation conditioning yields tolerant T-cells while preserving T-cell-dependent graft-versus-leukemia

et al. 2020

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Graft-versus-host disease (GvHD) remains a significant impediment to allogeneic hematopoietic cell transplantation (HCT) success, necessitating studies focused on alleviating GvHD, while preserving the graft-versus-leukemia (GvL) effect. Based on our previous studies showing bendamustine with total body irradiation (BEN-TBI) conditioning reduces GvHD compared to the current clinical standard of care cyclophosphamide (CY)-TBI in a murine MHC-mismatched bone marrow transplantation (BMT) model, this study aimed to evaluate the role and fate of donor T-cells following BEN-TBI conditioning. We demonstrate that BEN-TBI reduces GvHD compared to CY-TBI independently of T regulatory cells (Tregs). BEN-TBI conditioned mice have a smaller proportion and less activated donor T-cells, with lower CD47 expression, early post-transplant, but no sustained phenotypic differences in T-cells. In BEN-TBI conditioned mice, donor T-cells gain tolerance specific to host MHC antigens. Though these T-cells are tolerant to host antigens, we demonstrate that BEN-TBI preserves a T-cell-dependent GvL effect. These findings indicate that BEN-TBI conditioning reduces GvHD without compromising GvL, warranting its further investigation as a potentially safer and more efficacious clinical alternative to CY-TBI.

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Section: Flow Cytometrymentioning

confidence: 99%

Bendamustine with total body irradiation conditioning yields tolerant T-cells while preserving T-cell-dependent graft-versus-leukemia

et al. 2020

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“…Of note, anti-mouse Gr-1 clone RB6-8C5 has been shown to react strongly with Ly6G (a marker for granulocytic MDSCs) and more weakly with Ly6C (a marker for monocytic MDSCs), resulting in a delineated Gr-1 high population, representing the Ly6G + granulocytic MDSCs, and a Gr-1 mid population, representing the Ly6C + monocytic MDSCs [38]. To determine absolute cell numbers in blood, white blood cell counts were determined using a HemaVet 950 (Drew Scientific, Miami Lakes, FL) [39]. Cells were analyzed for reactive oxygen species (ROS) using a Cellular ROS Detection Assay Kit (Abcam, Cambridge, UK).…”

Section: Flow Cytometrymentioning

confidence: 99%

“…Cells were frozen in dry pellets before mRNA isolation using the RNeasy Kit (Qiagen, Hilden, Germany). cDNA was generated, and quantitative realtime polymerase chain reaction (qRT-PCR) was performed and analyzed as described previously [39,41].…”

Section: Quantitative Real-time Polymerase Chain Reactionmentioning

confidence: 99%

Bendamustine with Total Body Irradiation Limits Murine Graft-versus-Host Disease in Part Through Effects on Myeloid-Derived Suppressor Cells

Stokes

Hoffman

Molina

et al. 2019

Biology of Blood and Marrow Transplantation

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Graft-versus-host disease (GVHD) remains a significant challenge in allogeneic hematopoietic cell transplantation (HCT). An underinvestigated strategy to reduce GVHD is the modification of the preparative conditioning regimen. In the present study, we aimed to evaluate GVHD associated with bendamustine (BEN) conditioning in conjunction with total body irradiation (TBI) as an alternative to the standard myeloablative regimen of cyclophosphamide (CY) and TBI. We demonstrate that BEN-TBI conditioning, although facilitating complete donor chimerism, results in significantly less GVHD compared with CY-TBI. In BEN-TBI-conditioned mice, suppressive CD11b + Gr-1 high myeloid cells are increased in the blood, bone marrow, spleen, and intestines. When Gr-1 high cells are depleted before transplantation, the beneficial effects of BEN-TBI are partially lost. Alternatively, administration of granulocyte colony-stimulating factor, which promotes CD11b + Gr-1 + myeloid cell expansion, is associated with a trend toward increased survival in BEN-TBI-conditioned mice. These findings indicate a potential role of myeloid-derived suppressor cells in the mechanism by which BEN allows engraftment with reduced GVHD. BEN-TBI conditioning may present a safer alternative to CY-TBI conditioning for allogeneic HCT.

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“…In this knockout model, a significant increase in granulocytes in vivo was observed. Further work ( 66 ) determined that these granulocytic cells were indeed PMN-MDSCs based on their T cell suppressive behavior, and that the overall number and suppressive function of PMN-MDSCs from the conditional Pak2 knockout host was greater than that of the wild-type controls. Importantly, they identified that Pak2-deficiency sensitized myeloid progenitors to GM-CSF stimulation, which led to the accumulation of PMN-MDSCs.…”

Section: Transcriptional Regulators Of Pmn-mdscsmentioning

confidence: 99%

Granulocytic Myeloid-Derived Suppressor Cells as Negative Regulators of Anticancer Immunity

Kramer

Abrams

2020

Front. Immunol.

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The immune system plays a critical role in cancer progression and response to therapy. However, the immune system can be compromised during the neoplastic process. Notably, the myeloid lineage, which gives rise to granulocytic cells, including neutrophils, is a well-recognized target of tumor-mediated immune suppression. Ordinarily, granulocytic cells are integral for host defense, but in neoplasia the normal process of granulocyte differentiation (i.e., granulopoiesis) can be impaired leading instead to the formation of granulocytic (or PMN)-myeloid-derived suppressor cells (MDSCs). Such cells comprise various stages of myeloid differentiation and are defined functionally by their highly pro-tumorigenic and immune suppressive activities. Thus, considerable interest has been devoted to impeding the negative contributions of PMN-MDSCs to the antitumor response. Understanding their biology has the potential to unveil novel therapeutic opportunities to hamper PMN-MDSC production in the bone marrow, their mobilization, or their effector functions within the tumor microenvironment and, therefore, bolster anticancer therapies that require a competent myeloid compartment. In this review, we will highlight mechanisms by which the neoplastic process skews granulopoiesis to produce PMN-MDSCs, summarize mechanisms by which they execute their pro-tumorigenic activities and, lastly, underscore strategies to obstruct their role as negative regulators of antitumor immunity.

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Pak2 regulates myeloid-derived suppressor cell development in mice

Abstract: Key Points Pak2 negatively regulates CD11bhighGr1high MDSC development in mice via both cell-intrinsic and extrinsic mechanisms. Pak2 disruption activates STAT5 while downregulating the expression of IRF8, a well-described myeloid transcription factor.

Cited by 15 publications

References 57 publications

Bendamustine with total body irradiation conditioning yields tolerant T-cells while preserving T-cell-dependent graft-versus-leukemia

Bendamustine with total body irradiation conditioning yields tolerant T-cells while preserving T-cell-dependent graft-versus-leukemia

Bendamustine with Total Body Irradiation Limits Murine Graft-versus-Host Disease in Part Through Effects on Myeloid-Derived Suppressor Cells

Granulocytic Myeloid-Derived Suppressor Cells as Negative Regulators of Anticancer Immunity

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