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

AuthorsTeijeira, Alvaro; Garasa, Saray; Gato, María; Alfaro, Carlos; Migueliz, Itziar; Cirella, Assunta; Andrea, Carlos de; Ochoa, Maria Carmen; Otano, Itziar; Etxeberria, Iñaki; Andueza, María Pilar; Nieto, Celia P.; Resano, Leyre; Azpilikueta, Arantza; Allegretti, Marcello; Pizzol, María de; 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
KeywordsTumor-associated neutrophils
Neutrophil extracellular traps
Immune checkpoint blockade
Issue Date19-May-2020
CitationImmunity 52(5): 856-871.e8 (2020)
AbstractExtrusion of neutrophil extracellular traps (NETs) constitutes an adhesive mechanism employed by polymorphonuclear leukocytes in microbial defense and plays a role in cancer metastasis. Teijeira et al. show that intratumoral NETs protect malignant cells against cytotoxic attacks of the immune system, such as those elicited by checkpoint-based immunotherapy.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.
Publisher version (URL)http://dx.doi.org/10.1016/j.immuni.2020.03.001
Appears in Collections:(CNB) Artículos
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