Neutrophil extracellular traps induced by IL-8 promote diffuse large B cell lymphoma progression via the TLR9 signaling

Purpose: Over 30% of patients with diffuse large B cell lymphoma (DLBCL) experience treatment failure after first-line therapy. Neutrophil extracellular traps (NETs), a pathogen-trapping structure in tumor microenvironment, can promote the transition of autoimmunity to lymphomagenesis. Here, we investigate whether NETs play a novel role in DLBCL progression and its underlying mechanism. Experimental Design: NETs in DLBCL tumor samples and plasma were detected by immunofluorescence and ELISA, respectively. The correlation between NETs and clinical features were analyzed. The effects of NETs on cellular proliferation and migration and mechanisms were explored. And the mechanism of NET formation was also studied by a series of in vitro and in vivo assays. Results: Higher levels of NETs in plasma and tumor tissues were associated with dismal outcome in DLBCL patients. Further, we identified NETs increased cell proliferation and migration in vitro and tumor growth and lymph nodal dissemination in vivo. Mechanistically, DLBCL-derived IL-8 interacted with its receptor (CXCR2) on neutrophils, resulting in the formation of NETs via Src, p38 and ERK signaling. Newly formed NETs directly upregulated the Toll-like receptor 9 (TLR9) pathways in DLBCL and subsequently activated NF-B, STAT3 and p38 pathways to promote tumor progression. More importantly, disruption of NETs, blocking IL-8-CXCR2 axis or inhibiting TLR9 could retard tumor progression in preclinical models. Conclusions: Our data reveal a tumor-NETs aggressive interaction in DLBCL, and indicate that NETs is a useful prognostic biomarker and targeting this novel crosstalk represents a new therapeutic opportunity in this challenging disease.

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