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.
Highlights
Ruxolitinib was recently FDA-approved for the treatment of steroid-refractory aGVHD, based on REACH-1 and REACH-2 trial results that showed overall response rates of 55–62%, which are significantly greater than those observed with former “standard of care” options [5,6]
The pathophysiology of aGVHD has been connected to a 3-phase process: (1) initial tissue damage from the conditioning regimen, which activates host antigen-presenting cells (APC) by danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), (2) afferent phase characterized by the stimulation and proliferation of donor T cells in response to alloantigen expressed either on host APCs, labeled as direct antigen presentation, or on donor APCs, labeled as indirect presentation, and the (3) effector phase represented by generated donor T cell-mediated cytotoxic damage against host cells through Fas–Fas ligand interaction, perforin–granzyme, and TNF-α [45]
Factors related to inflammasome activation are produced during allo-HCT, including intestinal release of bacterial products and danger-associated molecules from dying cells that translocate into the internal milieu [32]
Summary
MDSCs derived from mobilization protocols can strongly suppress allo-responses mediated primarily by T cells and to a lesser degree by B cells and NK cells. The absence of GVHD in these patients has been associated with the infusion of MDSCs in these products [107]. The induction or maintenance of MDSC suppressive function would be beneficial in inhibiting inflammation associated with GVHD. Data from several studies propose the administration of ex vivo constructed MDSCs or in vivo interventions to achieve a desired suppressive state in vivo. Pathways involved in MDSC metabolism and the inflammasome signaling should be studied thoroughly in order to gain more knowledge regarding the applicability of these practices in the clinical setting. Translational studies are highly needed in this field to confirm the role of MDSC in the pathogenesis of GVHD.
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