Ozone-primed neutrophils promote early steps of tumour cell metastasis to lungs by enhancing their NET production.

Background: Air pollution, including particulates and gazes such as ozone (O ₃ ), is detrimental for patient's health and has repeatedly been correlated to increased morbidity and mortality in industrialised countries. Although studies have described a link between ambient particulate matter and increased lung cancer morbidity, no direct relation has yet been established between O ₃ exposure and metastatic dissemination to lungs.
Objectives: To outline the mechanisms through which pulmonary O ₃ exposure modulates metastasis kinetics in an experimental mouse model of O ₃ exposure.
Methods: Metastatic responses to pulmonary O ₃ exposure were assessed using a reliable experimental mouse model of concomitant pulmonary O ₃ exposure and tumour cell injection. Roles of neutrophils in O ₃ -induced lung metastasis were highlighted using blocking anti-Ly6G antibodies; moreover, the implication of neutrophil extracellular traps (NETs) in metastatic processes was evaluated using MRP8cre-Pad4lox/lox mice or by treating mice with DNase I.
Results: Pulmonary O ₃ exposure strongly facilitates the establishment of lung metastasis by (1) Inducing a pulmonary injury and neutrophilic inflammation, (2) Influencing very early steps of metastasis, (3) Priming neutrophils' phenotype to release NETs that favour tumour cell colonisation in lungs. The ability of O ₃ -primed neutrophils to enhance lung colonisation by tumour cells was proven after their adoptive transfer in Balb/c mice unexposed to O ₃ .
Conclusions: Pulmonary neutrophils induced by O ₃ promote metastatic dissemination to lungs by producing NETs. These findings open new perspectives to improve treatment and prevention strategies in patients affected by metastatic diseases.
Competing Interests: Competing interests: DC is the founder of Aquilon Pharmaceuticals, received speaker fees from AstraZeneca, Boehringer-Ingelheim, Novartis, MundiPharma, Chiesi and GSK and received consultancy fees from AstraZeneca, Boehringer-Ingelheim, and Novartis for the participation to advisory boards. None of these activities have any connection with oncology or development of drugs in the field of oncology.
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