Increased Frequencies Of Myeloid-Derived Suppressor Cells and Regulatory T-Cells Decrease Response To Donor Lymphocyte Infusions, Independent Of Graft Versus Host Disease In Multiple Myeloma

Allogeneic stem cell transplantation (allo-SCT) followed by donor lymphocyte infusions (DLI) can induce durable responses in multiple myeloma (MM) by virtue of the graft versus myeloma (GvM) effect. However, this is only true for a minority of patients and relapse rates after reaching an initial remission remain high. Also, transplant-related mortality and Graft-versus-Host-Disease (GvHD) are still major complications. Towards improving cellular immunotherapy we set out to identify the immune cell subsets that are involved in the GvM effect and GvHD.

Myeloid-Derived Suppressor Cells (MDSCs) are a heterogeneous population of bone marrow-derived myeloid cells, with strong immunosuppressive capacity. In general, they are divided into monocyte-like M-MDSCs en granulocyte-like G-MDSCs. In myeloma, they have been shown to be present in increased frequencies, inhibit T-cell proliferation and promote multiple myeloma cell growth in vitro. Furthermore, regulatory T-cells (T-regs) seem to suppress cellular anti-tumor responses in MM.

To determine whether MDSCs and T-regs hamper immunotherapy, we investigated MDSCs and T-regs in peripheral blood (PB) (n=43) from post-allo SCT MM patients, prior to their first DLI, and from healthy donors (n=13). All patients had persistent or progressive disease after allo-SCT. DLI dose was 10⁷ T-cells/kg for sibling donors (n=20) and 10⁶ T-cells/kg for matched unrelated donors (n=23).

We observed a significantly higher frequency of M-MDSCs (CD14⁺ HLA-DR^-/low) (mean 5.7 vs. 0.7%, P<0.001) and T-regs (CD4⁺ CD25⁺ CD127^-/low) (11.4 vs. 5.5%, P<0.01), but not of G-MDSCs (CD11b⁺ HLA-DR^-/low CD14^-CD33⁺) in PB of MM patients versus healthy donors. Interestingly, patients responding to DLI had significantly lower amounts of immunosuppressive G-MDSCs (mean 0.6 vs. 1.2%, P=0.04) and T-regs (7.9 vs. 13.9%, P=0.02) in their PB prior to DLI. There was no difference in M-MDSCs between responding and non-responding patients. This effect on GvM was independent of GvHD, as levels of G-MDSCs, M-MDSCs and T-regs did not differ between GvHD⁺ and GvHD^-groups.

We show that increased frequencies of G-MDSCs and T-regs are associated with resistance to DLI, independent of the occurrence of GvHD. Our data suggest that targeting G-MDSCs as well as T-regs may improve cellular immunotherapy in multiple myeloma.

van de Donk:Celgene: Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria.