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388 | JuNe 2020 | volume 19 An expansion of neutrophils in patients with cancer is usually associated with a poor prognosis. This is thought to be due to the ability of neutrophils to induce angiogenesis and mediate immunosuppression. Reporting in Immunity, Teijeira et al. now show that cancer cells can also subvert neutrophil functions by inducing the extrusion of neutrophil extracellular traps (NETs), which wrap around the tumour cells and protect them from T cellor natural killer (NK) cellmediated toxicity. NETosis is a peculiar form of cell death that is unique to neutrophils and results in the extrusion of DNA–protein complexes. It is induced by various stimuli, including chemotactic cues. The authors show that chemokines that are secreted by tumour cells induce NETosis in human neutrophils. This was dependent on the chemokine receptors CXCR1 and CXCR2, as inhibitors of these receptors, such as reparixin and pertussis toxin or blocking antibodies against CXCR1, prevented NETosis induction. To investigate the effects of NETs on tumour cells the authors created tumour spheroids from a colon carcinoma cell line and filmed their interactions with healthy donor allogeneic neutrophils. The spheroids induced NETosis, which was inhibited in the presence of reparixin. When tumour celltargeted cytotoxic lymphocytes (CTLs) and/or NK cells were added, tumour cell spheroids with NETs showed much better survival than spheroids that had been stripped of their NETs with DNAse I. In mice that received xenografted human tumour cell lines and human neutrophils, abundant NETs were detected in the tumours; however, these were reduced if the animals were treated with reparixin or pertussis toxin. The in vivo relevance of the protective role of NETs in tumours was demonstrated in mouse models of breast cancer (4T1) metastasis, where treatment of the animals with DNAse I or the PAD4 inhibitor GSK484, an inhibitor of NETosis, reduced the number of micrometastases. However, the treatment did not have any effect in mice that lacked both T cells and NK cells, confirming that NETs provide protection from these cells. In mice with established 4T1 tumours, treatment with GSK484 showed a synergistic effect with dual checkpoint inhibition (antiPD1 and antiCTLA4), and this was dependent on the presence of CTLs. Further in vitro experiments, as well as intravital microscopy in mice injected with Lewis lung carcinoma (LLC) cells, demonstrated that NETs reduce the physical contact between tumour cells and cytotoxic lymphocytes. This study shows that tumours induce the formation of NETs, which coat and thereby shield tumour cells against NK celland T cellmediated cytotoxicity. Moreover, it indicates that inhibitors of NETosis may be of value in combination with checkpoint inhibitors.