Tumor-derived Exosomal ENO2 Modulates Polarization of Tumor-associated Macrophages through Reprogramming Glycolysis to Promote Progression of Diffuse Large B-cell Lymphoma

Macrophages can be polarized into functional classically activated (M1) or alternatively activated (M2) phenotype. Tumor-associated macrophages (TAMs) mainly exhibit M2 phenotype. Previous works determined that up-regulation of enolase 2 (ENO2) in diffuse large B-cell lymphoma (DLBCL) cells can promote macrophages to an M2-like phenotype, thereby consequently promoting the progression of DLBCL. Exosomes are a subset of extracellular vesicles, carrying various bioactive molecules, mediate signals transduction and regulate immune cells. In our study, we investigated the role and related mechanisms of DLBCL-derived exosomal ENO2 in regulating macrophage polarization during DLBCL progression via bioinformatics analysis and a series of experiments. The results of bioinformatics analysis indicated that high expression of ENO2 was positively correlated with DLBCL progression and macrophages M2/M1 ratio. ENO2 protein levels were increased in the exosomes of the sera of DLBCL patients and DLBCL cells. Moreover, the DLBCL-derived exosomes were assimilated by macrophages and then regulated macrophage polarization. The results of in vitro and in vivo experiments showed that DLBCL-derived exosomal ENO2 modulated macrophages polarization (increased M2 phenotype and decreased M1 phenotype), thereby promoting DLBCL proliferation, migration, and invasion. We then revealed that the modulation of macrophages polarization by DLBCL-derived exosomal ENO2 depended on glycolysis and was promoted through GSK3β/β-catenin/c-Myc signaling pathway. These findings suggested that DLBCL-derived exosomal ENO2 accelerated glycolysis via GSK3β/β-catenin/c-Myc signaling pathway to ultimately promote macrophages to an M2-like phenotype, which can promote the proliferation, migration and invasion of DLBCL, suggesting that exosomal ENO2 may be a promising therapeutic target and prognostic biomarker for DLBCL.