The Expression And Clinical Significance Of Myeloid-derived Suppressor Cells In Multiple Myeloma Patients

BackgroundMechanisms of tumor immune escape are hotspots in the field of cancer research in recent years. The tumor cells evade host immune surveillance by several mechanisms. The suppressor cells with negative immune regulation function play an important role in tumor immune response. In recent years, the occurrence and development of tumors and inhibition of tumor induced cells have been widely studied. A group of myeloid derived suppressor cells(MDSCs), which have very close relationship to tumor progression, have attracted considerable attention in recent years in the field of oncology. Therefore, investgating the mechanism of MDSCs in tumor occurrence and development may help to diminish the inhibitory effect of MDSCs on the host tumor microenvironment and provide new ideas and strategies for the immunotherapy of tumor.Multiple myeloma(MM) is a hematologic cancer with malignant plasma cells abnormally accumulated within the bone marrow(BM). The introduction of three novel agents(lenalidomide, thalidomide and bortezomib) and autologous stem cell transplantation have improved therapeutic outcomes in MM, but it still remains incurable and often relapses due to minimal residual disease. Impaired immune function is a feature of MM patients and may contribute to tumorigenesis and disease progression. Tumor cells have evolved various mechanisms to evade the immune surveillance and generated an immunosuppressive microenvironment. Therefore, the novel therapies to improve anti-tumor immunity could be a novel approach to improve disease-free progression in MM patients.ObjectiveThe aim of this study is to examine the levels of MDSCs in both PB and BM from patients with MM, and to investigate the interaction between MM and MDSCs. Further exploring of the MDSCs in the occurrence and development of MM patients, we investgated the clinical evidences for MDSCs mediated immune escape, so as to provide new therapeutic targets for antitumor immunotherapy.MethodsA total of 93 patients diagnosed with MM from the First Affiliated Hospital(n=37) and Second Affiliated Hospital(n=56), Anhui Medical University, China were enrolled in this study. Blood and/or aspirates of bone marrow were collected from newly diagnosed(n=41), relapsed(n=12) and remission(n=40) [including complete remission(CR, n=9) and very good partial remission(VGPR, n=31)] MM patients. All newly diagnosed MM patients were diagnosd and classified according to the NCCN.In this experiment, we used CD14+HLA-DR-/low as the phenotype of MDSCs. The frequency and function of MDSCs with the relationship to the tumor development and outcome of therapy in MM were studied. Secondly, the analysis of MDSCs in newly diagnosed MM patients before and after treatment with bortezomib may provide the ideas for the clinical effect and prognosis for MM patients. Further experiments showed MM cell lines and normal human peripheral blood mononuclear cell cocultured may explore the possible sources for MDSCs in vitro.Results1. MDSCs were both detected in MM patients and normal human peripheral blood. The levels of MDSCs were increased significantly in both PB and BM from newly diagnosed MM patients compared with healthy controls in PB. When MM patients were grouped by types of monoclonal immunoglobulin, the levels of MDSCs in all groups were increased compared with healthy donors in PB, but nosignificant difference was observed among the groups defined by monoclonal immunoglobulin.2. The levels of MDSCs were associated with MM progression and outcome of therapy. There were increased levels of MDSCs in both blood and bone marrow in newly diagnosed and relapsed MM patients compared with remission MM patients and healthy donors. Patients had a higher ratio of peripheral blood MDSCs in stage Ⅲ patients than stageⅠ+Ⅱpatients. The frequency of MDSCs in patients with renal inadequacy was significantly increased compared with the patients with normal renal function. 20 newly diagnosed MM patients who received at least two cycles of bortezomib-based therapy were examined.The levels of MDSCs were significantly decreased after the bortezomib-based therapy3. The levels of Tregs were significantly increased in MM patients compared with healthy donors. There was no significant correlation between the frequency of MDSCs and Tregs.4. The plasma concentration of IL-6 was significantly increased in MM patients compared with healthy donors, while the Arginase-1, IL-10, TGF-β levels had no obvious difference.5. MM tumor cells can induce the accumulation of MDSCs from normal human peripheral blood mononuclear cells. MDSCs could proliferation by themselves.ConclusionThe levels of MDSCs were increased in patients with MM and were associated with tumor progression and outcome of therapy. MM cells promoted the accumulation of MDSCs directly and indirectly via plasma from MM patients.