2. Academic Validation
  3. CXCR1 and CXCR2 Chemokine Receptor Agonists Produced by Tumors Induce Neutrophil Extracellular Traps that Interfere with Immune Cytotoxicity

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

  • Immunity. 2020 May 19;52(5):856-871.e8. doi: 10.1016/j.immuni.2020.03.001.
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
Affiliations

Affiliations

  • 1 Program for Immunology and Immunotherapy Department, CIMA, Universidad de Navarra, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain. Electronic address: ateijeiras@unav.es.
  • 2 Program for Immunology and Immunotherapy Department, CIMA, Universidad de Navarra, 31008 Pamplona, Spain.
  • 3 Program for Immunology and Immunotherapy Department, CIMA, Universidad de Navarra, 31008 Pamplona, Spain; Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain.
  • 4 Program for Immunology and Immunotherapy Department, CIMA, Universidad de Navarra, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
  • 5 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain; Department of Oncology, Clinica Universidad de Navarra, 31008 Pamplona, Spain.
  • 6 Program for Immunology and Immunotherapy Department, CIMA, Universidad de Navarra, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain.
  • 7 Department of Oncology, Clinica Universidad de Navarra, 31008 Pamplona, Spain.
  • 8 Dompé Farmaceutici S.p.A., 20122 Milano, Italy.
  • 9 Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain; Department of Oncology, Clinica Universidad de Navarra, 31008 Pamplona, Spain.
  • 10 Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 11 Bristol Myers Squibb, Lawrence Township, NJ 08648, USA.
  • 12 Chemokine Signaling Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, Spain.
  • 13 Program for Immunology and Immunotherapy Department, CIMA, Universidad de Navarra, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Navarra Institute for Health Research (IDISNA), 31008 Pamplona, Spain. Electronic address: imelero@unav.es.
PMID: 32289253 DOI: 10.1016/j.immuni.2020.03.001
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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