The Role of Myeloid-Derived Suppressor Cells (MDSCs) in Graft-versus-Host Disease (GVHD)

Abstract

Background: Myeloid-derived suppressor cells (MDSCs) are implicated in the complex interplay involving graft-versus-leukemia (GVL) effects and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT) in hematologic malignancies.

Methods: A review of literature through PubMed was undertaken to summarize the published evidence on the pathophysiology and clinical implications of MDSCs in allo-HCT. Literature sources published in English since 1978 were searched, using the terms Natural Suppressor (NS) cells, MDSCs, GVHD, and allo-HCT.

Results: In vivo studies demonstrated that MDSCs derived from mobilization protocols could strongly suppress allo-responses mediated by T cells and enhance T-Reg activity, thus inhibiting GVHD toxicity. However, the influence of MDSCs on the GVL effect is not fully defined.

Conclusions: The induction or maintenance of MDSC suppressive function would be advantageous in suppressing inflammation associated with GVHD. Pathways involved in MDSC metabolism and the inflammasome signaling are a promising field of study to elucidate the function of MDSCs in the pathogenesis of GVHD and translate these findings to a clinical setting.

Keywords: GVHD; GVL; MDSCs; NS cells; allo-HCT.

Figure 1

Implications of MDSCs in GVHD. Myeloid-derived suppressor cells (MDSCs) are generated under inflammatory conditions. Inflammatory factors that induce MDSC recruitment and expansion include GM-CSF, G-CSF, M-CSF, and proinflammatory cytokines. Three different subsets of MDSCs have been identified according to their cellular markers; granulocytes, monocytes, and early stage MDSCs. The role of MDSC in the pathogenesis of GVHD would be beneficial through two mechanisms: (1) Immunosuppressive activity of MDSCs by regulating the secretion of various factors, among which ARG1, iNOS, and IDO; (2) Induction and expansion of T Regs. GM-CSF, granulocyte–macrophage colony-stimulating factor; G-CSF, granulocyte colony-stimulating factor; M-CSF, macrophage colony-stimulating factor; HSC, hematopoietic stem cells; HCT, hematopoietic cell transplantation; IFA, incomplete Freund’s adjuvant; RAPA, rapamycin; Gal-9, galectin-9; I-Arg, L-arginine; IFN-γ, interferon gamma; NO, nitric oxide; NLRP3, NLR pyrin family domain 3; AIM2, absent in melanoma 2; aGVHD, acute Graft-versus-Host Disease; ARG1, arginase 1; iNOS, inducible nitric oxide synthase; IDO, indoleamine 2,3-dioxygenase; ROS, reactive oxygen species; TGFβ, transforming growth factor beta; IL-6, IL-10, interleukin-6, interleukin-10.