The Role of Matrix Metalloproteinase-9 in Monocytic Myeloid-Derived Suppressor Cells in Allogeneic Hematopoietic Stem Cell Transplantation

Background: Myeloid-derived suppressor cells (MDSCs) have emerged as a heterogeneic immunoregulatory population that accumulate in large numbers during many pathologic conditions, including cancer, infectious diseases, trauma, and sepsis. Given that MDSCs are an important element of a cellular network regulating immune responses, their recovery early after allogeneic hematopoietic stem cell transplantation (allo-HSCT) seems to be related to regulating graft-versus-host disease (GVHD) and/or immune reconstitution. However, the nature of these cells remains controversial in terms of clinical allo-HSCT. Therefore, we conducted a large prospective analysis of patients undergoing allogeneic HSCT for hematologic malignancies to evaluate MDSC recovery and function in the proinflammatory milieu post-transplant, and its immune suppressive mechanisms.

Methods: We examined the expansion of circulating monocytic (M-) MDSCs and granulocytic (G-) MDSCs at the time of engraftment in 130 patients undergoing allo-HSCT. Further, we investigated differentially expressed genes between G-MDSCs and M-MDSCs by transcriptome resequencing and characterized the molecular functions using carboxyfluorescein succinimidyl ester (CFSE) assay.

Results: The high M-MDSC group had a higher infection rate within 100 days, worse 1-year cumulative incidence of treatment-related mortality (TRM) and 2-year probability of event-free survival (EFS) compared to those with low M-MDSC group. The frequency of M-MDSCs was associated with preceding severe mucositis. Transcriptome profiling analysis of 2 isolated subtypes of MDSCs showed that matrix metalloproteinase-9 (MMP-9) was expressed much more highly in M-MDSCs than in G-MDSCs. The high expression of MMP-9 (P<0.001)and its upstream genes, including ARRB2 (P = 0.010) and F2RL1 (P = 0.024), in M-MDSC was confirmed using qRT-PCR. Moreover, MMP-9 concentrations in cell lysates (P < 0.001) and in culture supernatants (P = 0.001) were much higher in M-MDSCs than G-MDSCs, as shown by ELISA.

Importantly, M-MDSCs isolated from patients post-HSCT had a higher capacity to suppress T cell responses than did G-MDSCs, and MMP-9 blockade more forcefully inhibited the immunosuppressive effect of M-MDSCs than that of G-MDSCs. Ultimately, the patients with high serum levels of MMP-9 had significantly higher infections within 100 days (P = 0.015), TRM by 1 year (P = 0.001) and a trend toward reduced EFS (P = 0.055) compared to those with low MMP-9.

Conclusion: Our data demonstrated that early expansion of M-MDSCs was associated with early infections and poorer clinical outcomes than was expansion of G-MDSCs. Post-HSCT M-MDSCs exhibited increased levels of matrix metalloproteinase-9 (MMP-9), which might play a key role in worsening post-transplant infections and, ultimately, survival outcomes.