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
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DOI：
10.1016/j.immuni.2020.03.001
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发表时间：
2020-05-19
期刊：
影响因子：
32.4
通讯作者：
Melero, Ignacio
中科院分区：
文献类型：
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作者：
Teijeira, Alvaro;Garasa, Saray;Melero, Ignacio
中性粒细胞在患有癌症的宿主中扩增并丰富。在CXCR1和CXCR2趋化因子受体激动剂和肿瘤产生的其他趋化因子的影响下，来自癌症患者的中性粒细胞和粒细胞骨髓源性抑制细胞（MDSC）挤出中性粒细胞胞外陷阱（NET）。在我们手中，CXCR1 和 CXCR2 激动剂被证明是癌症促进的 NETosis 的主要介质。 NETs 包裹并覆盖肿瘤细胞，并通过阻碍免疫细胞与周围靶细胞之间的接触，保护肿瘤细胞免受 CD8+ T 细胞和自然杀伤 (NK) 细胞介导的细胞毒性。 NET 保护肿瘤细胞免受细胞毒性，是小鼠癌症成功转移的基础，并且蛋白精氨酸脱亚胺酶 4 (PAD4) 抑制剂的免疫治疗协同作用可通过免疫检查点抑制剂抑制 NETosis。活体显微镜检查提供了中性粒细胞 NET 干扰细胞毒性 T 淋巴细胞 (CTL) 和 NK 细胞与肿瘤细胞接触的证据。
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.