Diffuse large B-cell lymphoma-derived exosomes push macrophage polarization toward M2 phenotype via GP130/STAT3 signaling pathway

Abstract

Growing evidence shows that cancer progression links with both heterogeneity of the tumor microenvironment and dysregulated activity of immune cells. Cancer-secreted exosomes are being recognized as indispensable mediators of the exchange cargo between cancer and immune cells. The M2-phenotype tumor-associated macrophages have the function of promoting tumor progression and drug resistance. Diffuse large B-cell lymphoma(DLBCL) is a highly heterogeneous and very common malignant non-Hodgkin's lymphoma. Here, we demonstrate that different subtype DLBCL cell-derived exosomes are internalized by macrophages, which can affect macrophages polarization. The mechanism of DLBCL-derived exosomes on macrophage polarization remains unclear currently. This study showed that DLBCL-secreted exosomes could induce the transformation of macrophages to a protumor M2-like phenotype, and block the drug-induced apoptosis of DLBCL cells in an indirect co-culture system. Different DLBCL-derived exosomes could change the phenotype of macrophages through the STAT3 signaling, which upregulated the expression of oncogenic genes and classical markers of M2-like phenotype macrophages, such as IL-10, CD206, and CD163. The addition of DLBCL-derived exosomes resulted in the activation of the STAT3 signaling pathway of M0/M2 macrophages in an indirect co-culture system. GP130 was highly enriched in DLBCL-derived exosomes, which triggered the activation of STAT3 of macrophages and subsequently induced the downstream targets such as BCL2, SURVIVIN, and BAX. The parallel changes of STAT3 and GP130 in macrophages confirmed that GP130 of DLBCL-derived exosomes promoted macrophage polarization by activating STAT3 signaling. Furthermore, all of these effects could be reversed by the GP130 inhibitor SC144. The data indicated that DLBCL-derived exosomes could trigger macrophages polarization into a pro-survival M2-like phenotype, which was at least partially through the GP130/STAT3 signaling pathway. Collectively, this study showed that DLBCL-derived exosomes could promote macrophages transformation to protumor M2-like phenotype in the tumor microenvironment.

Keywords: Diffuse large B-Cell lymphoma; Exosome; GP130; Macrophage; STAT3.