Identification of potential immune-related mechanisms related to the development of multiple myeloma

Background:Although significant advances have been made in the treatment of multiple myeloma(MM),leading to unprecedented response and survival rates among patients,the majority eventually relapse,and a cure remains elusive.This situation is closely related to an incomplete understanding of the immune microenvironment,especially monocytes/macrophages in patients with treatment-naïve MM.The aim of this study was to provide insight into the immune microenvironment,especially monocytes/macrophages,in patients with treatment-naïve MM.Methods:This study used the single-cell RNA sequencing(scRNA-seq)data of both patients with MM and heathy donors to identify immune cells,including natural killer(NK)cells,T cells,dendritic cells(DCs),and monocytes/macrophages.Transcriptomic data and flow cytometry analysis of monocytes/macrophages were used to further examine the effect of monocytes/macrophages in treatment-naïve MM patients.Results:A significant difference was observed between the bone marrow(BM)immune cells of the healthy controls and treatment-naïve MM patients through scRNA-seq.It is noteworthy that,through an scRNA-seq data analysis,this study found that interferon(IFN)-induced NK/T cells,terminally differentiated effector memory(TEMRA)cells,T-helper cells characterized by expression of IFN-stimulated genes(ISG^(+)Th cells),IFN-responding exhausted T cells,mannose receptor C-type 1(MRC1)^(+)DCs,IFN-responding DCs,MHCII^(+)DCs,and immunosuppressive monocytes/macrophages were enriched in patients with treatment-naïve MM.Significantly,transcriptomic data of monocytes/macrophages demonstrated that"don’t eat me"-related genes and IFN-induced genes increase in treatment-naïve MM patients.Furthermore,scRNA-seq,transcriptomic data,and flow cytometry also showed an increased proportion of CD16^(+)monocytes/macrophages and expression level of CD16.Cell-cell communication analysis indicated that monocytes/macrophages,whose related important signaling pathways include migration inhibitory factor(MIF)and interleukin 16(IL-16)signaling pathway,are key players in treatment-naïve MM patients.Conclusions:Our findings provide a comprehensive and in-depth molecular characterization of BM immune cell census in MM patients,especially for monocytes/macrophages.Targeting macrophages may be a novel treatment strategy for patients with MM.