Efficiency of human monocyte-derived suppressor cell-based treatment in graft-versus-host disease prevention while preserving graft-versus-leukemia effect

Abstract

Background Immunosuppressive cell-based therapy is a recent strategy for controlling Graft- versus -Host Disease (GvHD). Such cells ought to maintain their suppressive function in inflammatory conditions and in the presence of immunosuppressive agents currently used in allogeneic hematopoietic cell transplantation (allo-HCT). Moreover, these therapies should not diminish the benefits of allo-HCT, the Graft- versus -Leukemia (GvL) effect. We have previously reported on a novel subset of human monocyte-derived suppressor cells (HuMoSC) as a prospective approach for controlling GvHD.Objective The objective of this study was to explore the therapeutic relevance of the HuMoSC in clinical conditions. Methods Immune regulatory functions of HuMoSC were assessed in inflammatory conditions and in the presence of immunosuppressants. The therapeutic efficiency of the association of HuMoSC with immunosuppressants was evaluated in an experimental model of GvHD induced by human PBMC in NOD/SCID/IL2-Rγ c −/− (NSG) mice. Interestingly, the inhibitory functions of HuMoSC against T lymphocytes and their ability to polarize Treg are preserved, in vitro , in inflammatory environments and are not affected by immunosuppressive agents. In vivo , the association of HuMoSC-based treatment with an immunosuppressive drug showed a synergistic effect for controlling GvHD. Furthermore, HuMoSC control GvHD while preserving GvL effect in a xeno-GvHD conditioned mouse model with cell neoplasm (CAL-1). HuMoSC are generated according to good manufacturing practices (GMP) and we demonstrated that these cells tolerate long-term preservation with unaltered phenotype and function.Conclusion HuMoSC-based therapy represents a promising approach for controlling GvHD and could be quickly implemented in clinical practice.

Human Monocyte-Derived Suppressor Cell Supernatant Induces Immunoregulatory Effects and Mitigates xenoGvHD

“…We previously showed that CD33+HuMoSC efficiently inhibited T cell proliferation and induced Treg differentiation ( 5 ), independent of cell-to-cell contact. In fact, CD33+HuMoSC culture supernatant induced very strong anti-proliferative effect ( 4 ).…”

“…In contrast, mTGF, FasL and PD-L2 expression were very limited in both cells ( Figure 1E ). Considering that CD33+HuMoSC immunosuppressive properties were previously reported ( 4 , 5 ), we were interested in determining whether CD14+HuMoSC supernatant could provide similar effects. In this aim, total PBMC activated by CD3/CD28 beads were cultured in medium supplemented with increasing volumes of CD14+HuMoSC supernatant for five days.…”

“…CD33+HuMoSC generation has been described previously ( 4 , 5 ). Briefly, peripheral blood mononuclear cells (PBMC) were isolated from buffy coats of healthy donors by Ficoll density gradient centrifugation.…”

“…Our team has previously described an original approach to obtaining human myeloid suppressor cells derived from circulating monocytes (patent N°WO2015140077A1). These CD33-positive immunosuppressive cells were named human monocyte-derived suppressor cells (HuMoSC) ( 4 , 5 ). We showed that CD33+HuMoSC are able to efficiently inhibit T cell proliferation in a STAT3-dependent manner.…”

“…We showed that CD33+HuMoSC are able to efficiently inhibit T cell proliferation in a STAT3-dependent manner. In addition, they induce regulatory T cells (Treg) population and significantly prevent GvHD in a xenogeneic murine model without impairing graft-versus-leukemia effect ( 5 ). Moreover, CD33+HuMoSC did not required cell-to-cell contact to limit T cell proliferation and their culture supernatant induced a very strong anti-proliferative effect ( 4 ).…”