Although neutrophils have been linked to the formation of the pre-metastatic niche, the mechanism of their migration to distant, uninvolved tissues has remained elusive. We report that bone marrow neutrophils from mice with early-stage cancer exhibited much more spontaneous migration than that of control neutrophils from tumor-free mice. These cells lacked immunosuppressive activity but had elevated rates of oxidative phosphorylation and glycolysis, and increased production of ATP, relative to that of control neutrophils. Their enhanced spontaneous migration was mediated by autocrine ATP signaling through purinergic receptors. In ectopic tumor models and late stages of cancer, bone marrow neutrophils demonstrated potent immunosuppressive activity. However, these cells had metabolic and migratory activity indistinguishable from that of control neutrophils. A similar pattern of migration was observed for neutrophils and polymorphonuclear myeloid-derived suppressor cells from patients with cancer. These results elucidate the dynamic changes that neutrophils undergo in cancer and demonstrate the mechanism of neutrophils’ contribution to early tumor dissemination.
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We thank R. Ramakrishnan (H. Lee Moffitt Cancer Center) for the luciferase expressing LL2 tumor cell line; and D. Laxminarasimha for help in animal experiments. This work was supported by the Wistar Institute Animal and Bioinformatics core facilities and by the US National Institutes of Health (P01 CA140043 and T32 CA09171). S.Y. was supported by International Program for Ph.D Candidates, Sun Yat-Sen University, China.
The authors declare no competing interests.
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Patel, S., Fu, S., Mastio, J. et al. Unique pattern of neutrophil migration and function during tumor progression. Nat Immunol 19, 1236–1247 (2018). https://doi.org/10.1038/s41590-018-0229-5
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