Tumour-Derived Extracellular Vesicles Induce Diffuse Large B-Cell Lymphoma Progression Through Macrophage-Mediated MDSC Accumulation.

Elevated peripheral myeloid-derived suppressor cells (MDSCs) predicted suppressed anti-tumour immunity and poor prognosis in diffuse large B-cell lymphoma (DLBCL) patients. Here we demonstrated that tumour-derived extracellular vesicles (EVs) served as a messenger, delivering cholesterol from lymphoma cells to macrophages. Through internalisation of tumour-derived EVs, macrophages were activated and secreted IL-1β via the NLRP3/IL-1β axis, leading to IL-1β-mediated MDSC expansion, as well as T cell suppression and exhaustion in DLBCL. Furthermore, macrophage depletion in vitro and in vivo impeded MDSC infiltration induced by tumour-derived EVs. Pharmacological inhibition of cholesterol metabolism with metformin suppressed the secretion of EVs from DLBCL cells, accompanied by decreased IL-1β secretion and MDSC accumulation. Thus, we concluded that tumour-derived EVs induce MDSC accumulation in a macrophage-dependent manner and could be targeted by metformin through inhibition of cholesterol biogenesis in DLBCL.