Neutrophil-derived reactive oxygen species promote tumor colonization

Zhong et al. investigate how mutations in the NOX2 subunit Ncf1 lead to reduced ROS formation and affect B16F10 lung metastasis. The study highlights neutrophils as key to detrimental ROS-formation and suggest the involvement of IL-1 beta and RAGE. A single-nucleotide polymorphism of neutrophil cytosolic factor 1 (Ncf1), leading to an impaired generation of reactive oxygen species (ROS), is a causative genetic factor for autoimmune disease. To study a possible tumor protection effect by the Ncf1 mutation in a manner dependent on cell types, we used experimental mouse models of lung colonization assay by B16F10 melanoma cells. We observed fewer tumor foci in Ncf1 mutant mice, irrespective of alpha beta T, gamma delta T, B-cell deficiencies, or of a functional Ncf1 expression in CD68-positive monocytes/macrophages. The susceptibility to tumor colonization was restored by the human S100A8 (MRP8) promoter directing a functional Ncf1 expression to granulocytes. This effect was associated with an increase of both ROS and interleukin 1 beta (IL-1 beta) production from lung neutrophils. Moreover, neutrophil depletion by anti-Ly6G antibodies increased tumor colonization in wild type but failed in the Ncf1 mutant mice. In conclusion, tumor colonization is counteracted by ROS-activated and IL-1 beta-secreting tissue neutrophils.

Automated summary

The study shows that mutations in the Ncf1 gene reduce ROS formation, protecting against lung metastasis, with the involvement of IL-1 beta and RAGE in detrimental ROS formation by neutrophils.