Early Recovery of Myeloid-Derived Suppressor Cells After Allogeneic Hematopoietic Transplant: Comparison of Post-Transplantation Cyclophosphamide to Standard Graft-Versus-Host Disease Prophylaxis

Abstract

Allogeneic hematopoietic cell transplantation (alloHCT) using haploidentical donors (haploHCT) with post-transplantation cyclophosphamide (PTCy) for augmented graft-versus-host disease (GVHD) prophylaxis has emerged as a robust platform to expand donor options with acceptable levels of GVHD and graft failure. The mechanism by which PTCy mitigates GVHD risk is partly explained by preferential cytotoxicity based on aldehyde dehydrogenase levels and up-regulation of regulatory T cells, but is incompletely understood. Myeloid-derived suppressor cells are important mediators of T-cell function and are up-regulated by cyclophosphamide exposure. We hypothesized that this cell type may play a role in GVHD protection in children undergoing haploHCT/PTCy. We prospectively collected samples in the first month after alloHCT from children undergoing standard of care (SOC) alloHCT with matched donors and tacrolimus-based GVHD prophylaxis (N = 11) and PTCy recipients (N = 11). MDSC recovery was compared using flow cytometry, and MDSC suppressive function was assessed at the peak of MDSC quantitative recovery post-alloHCT. Groups were well matched for conditioning regimen and stem cell source. PTCy recipients exhibited more robust MDSC recovery, particularly polymorphonuclear-MDSCs than SOC recipients, with preservation of T-cell suppressive function. This corresponded to significantly lower incidence of Grade II to IV acute GVHD (9.1% versus 27.3%) and moderate/severe chronic GVHD (0% versus 27.3%) in PTCy recipients. Patients who developed GVHD had decreased MDSC-mediated T-cell suppression, as well as higher levels of IL-10, a cytokine closely linked to GVHD biology. Overall, these findings provide support for the role of MDSCs in mediating GVHD protection after PTCy-based haploHCT. © 2022 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Keywords: Haploidentical allogeneic hematopoietic cell transplant; Myeloid-derived suppressor cells; Post-transplantation cyclophosphamide.