Kinetics of Myeloid-Derived Suppressor Cells during Stem Cell Mobilization and Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma and Lymphoma Patients

Introduction:

Myeloid-derived suppressor cells (MDSC) are immunosuppressive immature cells of the myeloid lineage that play a role in cancer induction, progression and immune evasion. Two major subtypes of MDSC can be distinguished: the polymorphonuclear (PMN-MDSC) and monocytic (M-MDSC).

Immune reconstitution after autologous hematopoietic stem cell transplantation (ASCT) may play a role in the therapeutic effect of ASCT in multiple myeloma (MM) and lymphoma patients. Since MDSC are immunosuppressive cells, we postulate they might play a role in the immune reconstitution following ASCT. Here, we studied the effect of G-CSF mobilization on MDSC accumulation and the kinetics of MDSC during G-CSF mobilization and ASCT in MM and lymphoma patients.

Methods:

Flow cytometry was used to measure MDSC in the stem cell graft (SCG) and peripheral blood mononuclear cells (PBMC) of 9 MM and 4 aggressive lymphoma patients. PMN-MDSC were defined as CD11b⁺ CD33^dim HLA-DR^- CD15⁺ cells and M-MDSC as CD11b⁺ CD33⁺ HLA-DR^low/- CD14⁺ cells. MDSC were measured at G-CSF start, time of stem cell (SC) collection and following ASCT at predefined time points (day 0, day +14, day +28, day +100, day +360). Values are reported as mean percentage of MDSC of living cells. For SC mobilization, MM patients received high-dose cyclophosphamide and G-CSF, lymphoma patients received R-DHAP and G-CSF. 3/9 MM patients and 4/4 lymphoma patients had a complete response at the time of SC collection. As conditioning regimen MM patients received melphalan, lymphoma patients received BEAM.

Results:

In PBMC of both MM and lymphoma patients, G-CSF mobilization increased PMN-MDSC levels: 10.06% at start G-CSF vs 46.44% at SC collection in MM patients (p=0.0006); 19.65% at start G-CSF vs 50.74% at SC collection in lymphoma patients (p=0.1143). After ASCT, PMN-MDSC levels tended to decrease: 28.21% at day 0 vs 7.94% at day +180 in MM patients (p=0.1061); 40.35% at day 0 vs 2.32% at day +180 (p=0.2000) in lymphoma patients. This in contrast to M-MDSC levels, which were not influenced by the use of G-CSF: 5.77% at start G-CSF vs 3.67% at SC collection in MM patients (p=0.3704); 6.52% at start G-CSF vs 3.23% at SC collection in lymphoma patients (p=0.3429). M-MDSC levels remained rather stable during the transplant period, but tended to increase after ASCT: 3.80% at day 0 vs 8.81% at day +180 in MM patients (p=0.0417); 1.24% at day 0 vs 16.70% at day +180 in lymphoma patients (p=0.3333). When comparing MDSC levels in PBMC and the SCG, we observed a decrease in the PMN-MDSC/M-MDSC ratio in the SCG in MM patients (p=0.0078) and in lymphoma patients (p=0.1250). In the SCG, fewer PMN-MDSC and more M-MDSC were present as compared to PBMC. Interestingly, the expression of IL-4Rα on PMN-MDSC (p=0.0078) and M-MDSC (p=0.0078) in PBMC was increased after G-CSF, at time of SC collection.

Conclusion:

The kinetics of both MDSC subtypes were comparable between MM and lymphoma patients. G-CSF mobilization resulted in the accumulation of PMN-MDSC, but not of M-MDSC. In addition, the expression of IL-4Rα increased on both MDSC subtypes after G-CSF, indicating a potential higher immunosuppressive capacity of MDSC. In both MM and lymphoma patients, PMN-MDSC levels decreased after ASCT, whereas M-MDSC levels increased after ASCT. This might be due to the natural development of these cells. However, further research, including the effect of MDSC on immune reconstitution and the effect of G-CSF on the immunosuppressive capacity of MDSC, is warranted.