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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Data availability

The data that support the findings of this study are available from the corresponding author upon request. Source data are available for Figs. 18. RNAseq data were deposited in the GEO data repository under accession code GSE118366.

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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.

Author information

Author notes

    • Sima Patel

    Present address: Bristol-Myers Squibb, Lawrenceville, NJ, USA

    • George A. Dominguez

    Present address: ITUS Corporation, San Jose, CA, USA

  1. These authors contributed equally: Sima Patel, Shuyu Fu, Jerome Mastio.


  1. Immunology, Microenvironment, and Metastasis, Wistar Institute, Philadelphia, PA, USA

    • Sima Patel
    • , Shuyu Fu
    • , Jerome Mastio
    • , George A. Dominguez
    • , Abhilasha Purohit
    • , Andrew Kossenkov
    • , Cindy Lin
    • , Kevin Alicea-Torres
    • , Mohit Sehgal
    • , Yulia Nefedova
    • , Dario C Altieri
    •  & Dmitry I. Gabrilovich
  2. Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China

    • Shuyu Fu
    •  & Jie Zhou
  3. Sidney Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA

    • Lucia R. Languino
  4. University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    • Cynthia Clendenin
    •  & Robert H. Vonderheide
  5. Helen F Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA

    • Charles Mulligan
    • , Brian Nam
    • , Neil Hockstein
    • , Gregory Masters
    •  & Michael Guarino
  6. Molecular & Cellular Oncogenesis Programs, Wistar Institute, Philadelphia, PA, USA

    • Zachary T. Schug


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Investigation, S.P., S.F., J.M., G.D., A.P., C.L., K.A.-T. and M.S.; formal analysis, A.K. and Z.S.; resources, Y.N., L.R.L., C.C., R.H.V., C.M., B.N., N.H., G.M. and M.G.; writing (original draft), S.P. and G.D.; writing (review and editing), J.Z., D.C.A. and D.I.G.; funding acquisition, D.C.A. and D.I.G.; conceptualization and supervision, D.I.G.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Dmitry I. Gabrilovich.

Supplementary information

  1. Supplementary Information

    Supplementary Figures 1–8 and Supplementary Tables 1 and 2

  2. Reporting Summary

  3. Supplementary Video 1

    Time lapse video demonstrating spontaneous movement of neutrophils from naïve and RET TB mice. Scale bar = 50 µm

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