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. 2020 May 19;52(5):856-871.e8.
doi: 10.1016/j.immuni.2020.03.001. Epub 2020 Apr 13.

CXCR1 and CXCR2 Chemokine Receptor Agonists Produced by Tumors Induce Neutrophil Extracellular Traps that Interfere with Immune Cytotoxicity

Álvaro Teijeira  1 , Saray Garasa  2 , María Gato  3 , Carlos Alfaro  4 , Itziar Migueliz  2 , Assunta Cirella  2 , Carlos de Andrea  5 , Maria Carmen Ochoa  6 , Itziar Otano  3 , Iñaki Etxeberria  3 , Maria Pilar Andueza  7 , Celia P Nieto  2 , Leyre Resano  7 , Arantza Azpilikueta  4 , Marcello Allegretti  8 , Maria de Pizzol  8 , Mariano Ponz-Sarvisé  9 , Ana Rouzaut  6 , Miguel F Sanmamed  6 , Kurt Schalper  10 , Michael Carleton  11 , Mario Mellado  12 , María E Rodriguez-Ruiz  6 , Pedro Berraondo  6 , Jose L Perez-Gracia  7 , Ignacio Melero  13
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Free article

CXCR1 and CXCR2 Chemokine Receptor Agonists Produced by Tumors Induce Neutrophil Extracellular Traps that Interfere with Immune Cytotoxicity

Álvaro Teijeira et al. Immunity. .
Free article

Abstract

Neutrophils are expanded and abundant in cancer-bearing hosts. Under the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis. NETs wrap and coat tumor cells and shield them from cytotoxicity, as mediated by CD8+ T cells and natural killer (NK) cells, by obstructing contact between immune cells and the surrounding target cells. Tumor cells protected from cytotoxicity by NETs underlie successful cancer metastases in mice and the immunotherapeutic synergy of protein arginine deiminase 4 (PAD4) inhibitors, which curtail NETosis with immune checkpoint inhibitors. Intravital microscopy provides evidence of neutrophil NETs interfering cytolytic cytotoxic T lymphocytes (CTLs) and NK cell contacts with tumor cells.

Keywords: immune checkpoint blockade; neutrophil extracellular traps; tumor-associated neutrophils.

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Conflict of interest statement

Declaration of Interests Ignacio Melero reports receiving commercial research grants from BMS, Bioncotech, Alligator, Pfizer, Leadartis, and Roche; has received speakers bureau honoraria from MSD; and is a consultant or advisory board member for BMS, Roche, Genmab, F-Star, Bioncotech, Bayer, Numab, Pieris, Alligator, and Merck Serono. M.A. and M.d.P. are employees at Dompé Farmaceutici S.p.A., Italy. The company has interests in the development of CXCR1 and 2 allosteric modulator for the treatment of oncologic-related diseases. J.L.P.-G. reports research grants and support from Roche, BMS, MSD, Ipsen, Eisai, Incyte, and Janssen and is a consultant or advisory board member for Roche, BMS, Ipsen, Eisai, and MSD. M.P.-S. reports receiving commercial research grants from BMS and Roche and has received speaker’s bureau honoraria from Roche. M.C. is an employee of Mavupharma. The remaining authors declare no competing interests.

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