Neutrophil extracellular traps formed during chemotherapy confer treatment resistance via TGF-? activation

Metastasis is the major cause of cancer death, and the development of therapy resistance is common. The tumor microenvironment can confer chemotherapy resistance (chemoresistance), but little is known about how specific host cells influence therapy outcome. We show that chemotherapy induces neutrophil recruit-ment and neutrophil extracellular trap (NET) formation, which reduces therapy response in mouse models of breast cancer lung metastasis. We reveal that chemotherapy-treated cancer cells secrete IL-1(3, which in turn triggers NET formation. Two NET-associated proteins are required to induce chemoresistance: integrin-orv(31, which traps latent TGF-(3, and matrix metalloproteinase 9, which cleaves and activates the trapped latent TGF-(3. TGF-(3 activation causes cancer cells to undergo epithelial-to-mesenchymal transition and correlates with chemoresistance. Our work demonstrates that NETs regulate the activities of neighboring cells by trapping and activating cytokines and suggests that chemoresistance in the metastatic setting can be reduced or prevented by targeting the IL-1(3-NET-TGF-(3 axis.

Automated summary

Metastasis is a major cause of cancer death, often accompanied by therapy resistance. In this study, we discovered that chemotherapy induces neutrophil recruitment and NET formation, leading to reduced therapy response in breast cancer lung metastasis mouse models. We further elucidate that chemotherapy-treated cancer cells secrete IL-1(3, which triggers NET formation. NET-associated proteins, integrin-αv(β3 and matrix metalloproteinase 9, play crucial roles in activating latent TGF-β3 and promoting chemoresistance. Our findings suggest that targeting the IL-1(3-NET-TGF-β3 axis could potentially reduce or prevent chemoresistance in the metastatic setting.