Dynamic Change and Impact of Circulating Myeloid-Derived Suppressor Cells in Patients Following Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Yin Jin , Zhang Yicheng 
Published: October 2019

Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population involved in tumor-associated immunosuppression and played immune regulatory roles in malignancies, infectious disease, autoimmune disease, trauma and inflammatory disease. Based on the significant suppressive functions, MDSCs raises great interests in the field of allogenetic hematopoietic stem cell transplantation (allo-HSCT) and graft-versus-host disease (GVHD). In recent years, studies described the immunosuppressive functions of CD14+HLA-DR-/low MDSCs, one of the few well-characterized MDSC subsets in human. However, the studies in patients with allo-HSCT are still scanty. This study identified the phenotype of CD14+HLA-DR-/low MDSCs and systematically monitored the dynamic changes of MDSCs accumulation in patients during the first 100 days after allo-HSCT in order to evaluate possible effects of MDSCs on aGVHD development and clinical outcomes. We also detected the frequencies of other cell types and concentrations of relative cytokines during MDSCs accumulation. Results showed that accumulation of MDSCs in the graft and in peripheral blood when engraftment might contribute to patients' overall immune suppression and result in the successful control of severe aGVHD and long-term survival without influence on risk of recurrence after allo-HSCT. However, the level of MDSCs in the graft had more favorable predictive abilities compared with that in PBMCs when engraftment. Furthermore, MDSCs frequencies were significantly increased in patients developing aGVHD after allo-HSCT.
In the patients with mild aGVHD (0-2), MDSCs accumulated at the time of engraftment after allo-HSCT and decreased to basal levels at about 4 weeks. MDSCs frequencies would keep in stable levels with slight fluctuations in the following weeks. But, in patients with severe aGVHD (3-4), MDSCs elevated slightly when engraftment. When aGVHD occurred, MDSCs frequencies would significantly increase. And a synchronized reduction of the levels of MDSCs was observed after effective management of aGVHD with immunosuppressive therapy. Besides, the levels of IL-10, IL-6, TNF-α, Arg-1, iNOS and HO-1 increased greatly both in patients with aGVHD and in high MDSCs group. It is speculated that MDSC accumulation at the onset of aGVHD might be caused by secondary inflammatory response, especially related to high concentrations of IL-6 and TNF-α. But the accumulation would not be able to counterbalance the aggravation of aGVHD and would not have influence on clinical outcomes and risk of relapse in future. Overall, we suggested that MDSCs might be considered as a potential new approaches to regulate transplant rejection and achieve the recipient host long-term acceptance and survival.
Figure 1. Frequencies of cell subsets in the graft. Frequencies of MDSCs in the graft were compared between normal controls and patients grouped by aGVHD (i) and aGVHD scores Figure 1. Frequencies of cell subsets in the graft. Frequencies of MDSCs in the graft were compared between normal controls and patients grouped by aGVHD (i) and aGVHD scores Figure 2. Increased frequencies of MDSCs in PBMCs of patients after allo-HSCT. (A) At the time of engraftment, the levels of MDSCs in PBMCs were compared between patients and normal controls (i), and were further analyzed according to aGVHD scores (ii). (B) After allo-HSCT, comparisons of MDSCs frequencies were performed between patients and normal controls grouped by aGVHD (i) and aGVHD severity (ii). (C) The dynamic changes of MDSCs frequencies after allo-HSCT were monitored in patients with aGVHD (i) and were analyzed based on aGVHD scores (ii). (D) The systematic monitoring of MDSCs frequencies was performed in all patients during the first 100 days after allo-HSCT grouped by aGVHD scores (i) and aGVHD severity (ii). Figure 2. Increased frequencies of MDSCs in PBMCs of patients after allo-HSCT. (A) At the time of engraftment, the levels of MDSCs in PBMCs were compared between patients and normal controls (i), and were further analyzed according to aGVHD scores (ii). (B) After allo-HSCT, comparisons of MDSCs frequencies were performed between patients and normal controls grouped by aGVHD (i) and aGVHD severity (ii). (C) The dynamic changes of MDSCs frequencies after allo-HSCT were monitored in patients with aGVHD (i) and were analyzed based on aGVHD scores (ii). (D) The systematic monitoring of MDSCs frequencies was performed in all patients during the first 100 days after allo-HSCT grouped by aGVHD scores (i) and aGVHD severity (ii).

Disclosures
No relevant conflicts of interest to declare.