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

被引：555

作者：

Teijeira, Alvaro ^{[1
,2
,3
,4
]}

Garasa, Saray ^{[1
,2
]}

Gato, Maria ^{[1
,2
,4
]}

Alfaro, Carlos ^{[1
,2
,3
]}

Migueliz, Itziar ^{[1
,2
]}

Cirella, Assunta ^{[1
,2
]}

de Andrea, Carlos ^{[3
,4
,5
]}

Carmen Ochoa, Maria ^{[1
,2
,3
,4
]}

Otano, Itziar ^{[1
,2
,4
]}

Etxeberria, Inaki ^{[1
,2
,4
]}

Pilar Andueza, Maria ^{[5
]}

Nieto, Celia P. ^{[1
,2
]}

Resano, Leyre ^{[5
]}

Azpilikueta, Arantza ^{[1
,2
,3
]}

Allegretti, Marcello ^{[6
]}

de Pizzol, Maria ^{[6
]}

Ponz-Sarvise, Mariano ^{[4
,5
]}

Rouzaut, Ana ^{[1
,2
,3
,4
]}

Sanmamed, Miguel F. ^{[1
,2
,3
,4
]}

Schalper, Kurt ^{[7
]}

Carleton, Michael ^{[8
]}

Mellado, Mario ^{[9
]}

Rodriguez-Ruiz, Maria E. ^{[1
,2
,3
,4
]}

Berraondo, Pedro ^{[1
,2
,3
,4
]}

Perez-Gracia, Jose L. ^{[5
]}

Melero, Ignacio ^{[1
,2
,3
,4
]}

机构：

[1] Univ Navarra, Program Immunol, CIMA, Pamplona 31008, Spain

[2] Univ Navarra, Immunotherapy Dept, CIMA, Pamplona 31008, Spain

[3] Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain

[4] Navarra Inst Hlth Res IDISNA, Pamplona 31008, Spain

[5] Clin Univ Navarra, Dept Oncol, Pamplona 31008, Spain

[6] Dompe Farmaceut SpA, I-20122 Milan, Italy

[7] Yale Univ, Dept Pathol, Sch Med, New Haven, CT 06520 USA

[8] Bristol Myers Squibb, Lawrence Township, NJ 08648 USA

[9] Ctr Nacl Biotecnol CNB CSIC, Dept Immunol & Oncol, Chemokine Signaling Grp, Madrid 28049, Spain

来源：

IMMUNITY | 2020年 / 52卷 / 05期

关键词：

METASTATIC MELANOMA; PERIPHERAL-BLOOD; SUPPRESSOR-CELLS; DNA TRAPS; INHIBITION; INNATE; MOUSE; PAD4;

D O I：

10.1016/j.immuni.2020.03.001

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：856 / +

页数：24

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