Rapamycin-based graft-versus-host disease prophylaxis increases the immunosuppressivity of myeloid-derived suppressor cells without affecting T cells and anti-tumor cytotoxicity

Abstract

The immunosuppressant rapamycin (RAPA) inhibits mammalian target of rapamycin (mTOR) functions and is applied after allogeneic bone marrow transplantation (BMT) to attenuate the development of graft-versus-host disease (GVHD), although the cellular targets of RAPA treatment are not well defined. Allogeneic T cells are the main drivers of GVHD, while immunoregulatory myeloid-derived suppressor cells (MDSCs) were recently identified as potent disease inhibitors. In this study, we analyzed whether RAPA prevents the deleterious effects of allogeneic T cells or supports the immunosuppressive functions of MDSCs in a BMT model with major histocompatibility complex (MHC) classes I and II disparities. RAPA treatment efficiently attenuated clinical and histological GVHD and strongly decreased disease-induced mortality. Although splenocyte numbers increased during RAPA treatment, the ratio of effector T cells to MDSCs was unaltered. However, RAPA treatment induced massive changes in the genomic landscape of MDSCs preferentially up-regulating genes responsible for uptake or signal transduction of lipopeptides and lipoproteins. Most importantly, MDSCs from RAPA-treated mice exhibited increased immunosuppressive potential, which was primarily inducible nitric oxide synthase (iNOS)-dependent. Surprisingly, RAPA treatment had no impact on the genomic landscape of T cells, which was reflected by unchanged expression of activation and exhaustion markers and cytokine profiles in T cells from RAPA-treated and untreated mice. Similarly, T cell cytotoxicity and the graft-versus-tumor effect were maintained as co-transplanted tumor cells were efficiently eradicated, indicating that the immunosuppressant RAPA might be an attractive approach to strengthen the immunosuppressive function of MDSCs without affecting T cell immunity.

Graft-Versus-Host Disease Prevention by In Vitro-Generated Myeloid-Derived Suppressor Cells Is Exclusively Mediated by the CD11b+CD11c+ MDSC Subpopulation

“…One day before BMT, B6.bm1 recipient mice received total body irradiation with 12 Gy split in two doses 3 h apart from a 137 Cs source. BM cells were depleted from T cells as described previously ( 18 , 19 ). Mice were intravenously reconstituted with 5 × 10 6 T-cell-depleted BM (TCD-BM) in the presence or absence of 2 × 10 7. spleen cells (SC).…”

“…The original contributions presented in the study are publicly available and are based on JS's dissertation: ( 60 ). mRNA Seq data can be found here: .…”

“…Different precursor cells and cytokine combinations are suitable for in vitro induction and expansion of MDSCs. While Zhou et al used mouse embryonic stem cells activated with a mixture of cytokines in a three-step differentiation strategy (17), MDSCs currently are mostly induced by culturing unseparated BM cells in GM-CSF alone or in combinations with cytokines such as G-CSF or IL-13 (18)(19)(20). Independent of the cytokine combination used, adoptive transfer of in vitro-generated MDSCs efficiently prevents GVHD induction, while tumor reactivity in MDSC-treated mice is maintained.…”

The Role of Myeloid-Derived Suppressor Cells (MDSCs) in Graft-versus-Host Disease (GVHD)

“…In vivo studies showed that rapamycin was able to induce G-MDSCs accumulation with an enhanced immunosuppressive role in the presence of aGVHD, via upregulation of ARG1 and iNOS and induction of regulatory T cells. Graft-versus-tumor effect was maintained [ 57 , 58 ].…”

“…In addition, under inflammatory conditions, T Regs may promote immunosuppression by the differentiation of MDSC toward M-MDSCs ( p < 0.01, ANOVA and Tukey post-test) [ 101 ]. The use of rapamycin is shown to be feasible in aGVHD management when the immunosuppressive capacity of MDSCs needs to be strengthened without impairing T cell-mediated fitness [ 57 , 58 ]. Supported by these data, it is logical for someone to consider that the adoptive transfer of a product containing both mobilized MDSCs and T Regs may provide greater benefit for achieving immune tolerance than either alone.…”