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

• Published in: Immunity (Cambridge, Mass.) Vol. 52; no. 5; pp. 856 - 871.e8
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19-05-2020; Elsevier Limited
• Subjects: Agonists; Animals; Arginine; Arginine deiminase; Blocking; Cancer; CD8 antigen; Cell Line, Tumor; Chemokines; Chemotactic factors; CXCR2 protein; Cytotoxicity; Cytotoxicity, Immunologic - immunology; Deoxyribonucleic acid; DNA; Extracellular Traps - metabolism; HT29 Cells; Humans; immune checkpoint blockade; Immune checkpoint inhibitors; Immune system; Inhibitors; Intravital Microscopy - methods; Killer Cells, Natural - immunology; Leukocytes (neutrophilic); Ligands; Lymphocytes; Lymphocytes T; Metastases; Metastasis; Mice; Natural killer cells; Neoplasms, Experimental - immunology; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - therapy; neutrophil extracellular traps; Neutrophils; Receptors; Receptors, Chemokine - agonists; Receptors, Chemokine - immunology; Receptors, Chemokine - metabolism; Receptors, Interleukin-8A - agonists; Receptors, Interleukin-8A - immunology; Receptors, Interleukin-8A - metabolism; Receptors, Interleukin-8B - agonists; Receptors, Interleukin-8B - immunology; Receptors, Interleukin-8B - metabolism; Suppressor cells; T-Lymphocytes, Cytotoxic - immunology; Thrombosis; Toxicity; Tumor cells; tumor-associated neutrophils; Tumors; tumor-associated neutrophils; neutrophil extracellular traps; immune checkpoint blockade
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2020.03.001

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.
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•Tumor-secreted CXCR1 and CXCR2 ligands induce extrusion of NETs•NETs protect tumor cells from CTL and NK cytotoxicity in 3D cultures•Inhibition of NETosis sensitizes tumors to PD-1+CTLA-4 dual checkpoint blockade•NETs impair contact of immune cytotoxic cells with tumor cells in living mice
Extrusion 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.