Tumour‐derived exosomes promote the induction of monocytic myeloid‐derived suppressor cells from peripheral blood mononuclear cells by delivering miR‐106a‐5p and miR‐146a‐5p in multiple myeloma

Abstract

SummaryThe shift of the tumour immune microenvironment to a suppressive state promotes not only the development and progression of the disease in multiple myeloma (MM) but also the development of resistance to immunotherapy. We previously demonstrated that myeloma cells can induce monocytic myeloid‐derived suppressor cells (M‐MDSCs) from healthy peripheral blood mononuclear cells (PBMCs) via the concomitant secretion of CC motif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF), but an unknown mediator also promotes M‐MDSC induction. This study demonstrates that miR‐106a‐5p and miR‐146a‐5p delivered by tumour‐derived exosomes (TEXs) from myeloma cells play essential roles in M‐MDSC induction in MM. MiR‐106a‐5p and miR‐146a‐5p upregulate various immunosuppressive/inflammatory molecules in PBMCs, such as IDO1, CD38, programmed death‐ligand 1, CCL5 or MYD88, which are involved in interferon (IFN)‐α response, IFN‐γ response, inflammatory response, tumour necrosis factor‐α signalling and Interleukin‐6‐JAK–STAT3 signalling. These molecular features mirror the increases in myeloid cellular compartments of PBMCs when co‐cultured with myeloma cells. MiR‐106a‐5p and miR‐146a‐5p have a compensatory relationship, and these two miRNAs collaborate with CCL5 and MIF to promote M‐MDSC induction. Collectively, novel therapeutic candidates may be involved in TEX‐mediated sequential cellular and molecular events underlying M‐MDSC induction, potentially improving the efficacy of immunotherapy.

Pathways to therapy resistance: The sheltering effect of the bone marrow microenvironment to multiple myeloma cells

“…Experiments have demonstrated that exosomes derived from BMSCs provide a safeguard against bortezomib by activating certain proteins (c-Jun, p38, p53, AKT) and influencing the expression of Bcl-2, caspase 9, caspase 3, and PARP [ 145 ]. In addition, exosomes have the ability to influence the immune response in the BMME, creating a suppressive environment that enables myeloma cells to avoid detection by the immune system and continue to survive even after treatment [ 146 ]. Furthermore, exosomes play a role in the survival of MDSCs by activating STAT3 and enhancing their immunosuppressive characteristics [ 147 , 148 ].…”