Multistep molecular trajectory of monocytic myeloid-derived suppressor cell induction by diffuse large B-cell...

This study aimed to investigate how tumor cells from diffuse large B-cell lymphoma (DLBCL) induce monocytic myeloid-derived suppressor cells (M-MDSCs) from normal peripheral blood mononuclear cells (PBMCs), using an indirect co-culture system that involves normal PBMCs and four human DLBCL -derived cell lines (HDBCLs). All four HDBCLs secreted macrophage migration inhibitory factor (MIF), and two HDBCLs with a stronger ability to induce M-MDSCs also secreted interleukin-10 (IL-10). We revealed that MIF plays a crucial but preparatory role in M-MDSC induction, as its inhibition strongly suppressed M-MDSC formation, whereas recombinant MIF alone exhibited only minimal inductive activity. In contrast, neutralizing IL-10 in IL-10-secreting HDBCLs suppressed M-MDSC induction, whereas adding recombinant IL-10 to IL-10-non-secreting HDBCLs enhanced it, indicating that IL-10 has a more facilitative role. Gene sets associated with the inflammatory response and tumor necrosis factor-α signaling, along with inflammatory molecules, such as IL-1α, were upregulated in the CD33⁺ myeloid fraction of PBMCs at 24 h, before decreasing at 96 h, in co-cultures with HDBCLs that do not secrete IL-10. Furthermore, recombinant IL-10 further downregulated these inflammatory signals while enhancing M-MDSC induction. This indicates that the multistep molecular process of M-MDSC induction from PBMCs by the co-presence of HDBCLs begins with a transient early hyper-inflammatory phase and transitions into a post-inflammatory immunosuppressive phase. Our study demonstrates that treatments that target specific molecular phases regulated by cytokines could reduce M-MDSC induction and improve the effectiveness of immune cell therapy.