Immunity · 2020
CXCR1 and CXCR2 Chemokine Receptor Agonists Produced by Tumors Induce Neutrophil Extracellular Traps that Interfere with Immune Cytotoxicity.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Teijeira Álvaro, Garasa Saray, Gato María, Alfaro Carlos, Migueliz Itziar, Cirella Assunta, de Andrea Carlos, Ochoa Maria Carmen, Otano Itziar, Etxeberria Iñaki, Andueza Maria Pilar, Nieto Celia P, Resano Leyre, Azpilikueta Arantza, Allegretti Marcello, de Pizzol Maria, Ponz-Sarvisé Mariano, Rouzaut Ana, Sanmamed Miguel F, Schalper Kurt, Carleton Michael, Mellado Mario, Rodriguez-Ruiz María E, Berraondo Pedro, Perez-Gracia Jose L, Melero Ignacio
Аннотация
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.