Matrix Metalloproteinase-9 in Monocytic Myeloid-Derived Suppressor Cells Correlate with Early Infections and Clinical Outcomes in Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

The recovery of myeloid-derived suppressor cells (MDSCs) and its relevance in clinical acute graft-versus-host disease (GVHD) and post-hematopoietic stem cell transplantation (HSCT) infections remain to be fully characterized. We examined the expansion of circulating monocytic (M-) MDSCs and granulocytic (G-) MDSCs at the time of engraftment in 130 patients undergoing allogeneic HSCT (allo-HSCT). Compared with the G-MDSC group, the high M-MDSC group had a higher infection rate within 100 days, along with worse 1-year cumulative incidence of treatment-related mortality (TRM) and 2-year probability of event-free survival (EFS). The frequency of M-MDSCs was associated with preceding severe mucositis. Transcriptome profiling analysis of 2 isolated MDSC subtype showed significantly greater matrix metalloproteinase-9 (MMP-9) expression in M-MDSCs than in G-MDSCs. M-MDSCs produced abundantly more MMP-9. Importantly, compared with G-MDSCs, M-MDSCs isolated from patients post-HSCT had a greater capacity to suppress T cell responses, and MMP-9 blockade more forcefully inhibited their immunosuppressive effect. MMP-9 levels also were associated with the occurrence of infections and with transplantation outcomes. Based on these findings, we identify M-MDSCs as a major contributor to infections early after allo-HSCT and worse clinical outcomes via MMP-9.

Early Plasma Matrix Metalloproteinase Profiles. A Novel Pathway in Pediatric Acute Respiratory Distress Syndrome

“…In this study, we found that MMP profile 1 was common among pediatric cancer/HCT patients. Emerging evidence suggests that monocyte myeloid-derived suppressor cells produce significant quantities of MMP-9 post-HCT and that neutropenic mice are deficient in pulmonary MMP-9; we therefore speculate that post-transplant immune reconstitution of these cellular lineages may play a role in ARDS (44,55). In our study, aMMP-9 was associated with mortality independent of P/F ratio but not independent of cancer/HCT status, and because total and aMMP-9 levels were strongly depressed in cancer/HCT patients, this suggests a potential pathobiologic pattern largely unique to this patient group.…”

Myeloid-Derived Suppressor Cells in the Context of Allogeneic Hematopoietic Stem Cell Transplantation

“…-early expansion of M-MDSCs was associated with a higher early infection incidence, a higher NRM, and a lower EFS (and/or higher relapse incidence = RI), but did not affect OS. -early expansion of M-MDSCs was not associated with acute GVHD in patients that received transplants from siblings or matched unrelated donors (51,53). Lower expansion of M-MDSCs after allo-HSCT was associated with severe acute GVHD in a cohort of patients that received transplants from siblings, matched unrelated donors, haploidentical-related donors, and double cord donors (52) ( Table 2).…”

“…In humans, MDSCs have been related to worse outcomes in hematological malignancies (60,61); therefore, MDSCs were suspected to be involved in relapses after allo-HSCT. However, in the allo-HSCT setting, only a few prospective studies have reported a significantly higher probability of relapse in patients with higher M-MDSC frequencies than other patients, in the 30 days following allo-HSCT (52,53). Other studies suggested that MDSCs preserved the GVT effect (26,56).…”

Engineering CAR-T Cells for Improved Function Against Solid Tumors

“…Inhibition of mTOR with rapamycin led to decreased tumor growth via lower glycolytic and suppressive activity of MDSCs. Similarly to CAFs, MDSCs may also be important for tumor metastasis by remodeling the extracellular matrix via production of MMP9 ( 49 ).…”