The Nlrp3 Inflammasome Suppresses Colorectal Cancer Metastatic Growth in the Liver by Promoting Natural Killer Cell Tumoricidal Activity
The Nlrp3 Inflammasome Suppresses Colorectal Cancer Metastatic Growth in the Liver by Promoting Natural Killer Cell Tumoricidal Activity
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DOI：
10.1016/j.immuni.2015.08.013
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发表时间：
2015-10-20
期刊：
影响因子：
32.4
通讯作者：
Saleh, Maya
中科院分区：
文献类型：
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作者：
Dupaul-Chicoine, Jeremy;Arabzadeh, Azadeh;Saleh, Maya
炎症和肿瘤发生之间的相互作用现在已经明确。然而，炎症是如何在转移性环境中引起的，以及先天免疫途径在抑制继发部位肿瘤生长中的相应作用还知之甚少。在这里，我们表明，小鼠缺乏Nlrp 3炎性体成分加剧了肝结直肠癌转移性生长，这是由受损的白细胞介素-18（IL-18）信号转导介导的。肿瘤生长的控制不依赖于不同的癌细胞定植或增殖、肠道微生物群效应或适应性免疫系统的杀肿瘤活性。相反，炎性体-IL-18途径影响肝NK细胞的成熟、死亡配体FasL的表面表达以及杀死FasL敏感性肿瘤的能力。我们的研究结果定义了先天免疫系统内的调节信号通路，该通路将炎性小体激活与抑制结肠直肠癌在肝脏中生长所需的有效NK细胞介导的肿瘤攻击联系起来。
The crosstalk between inflammation and tumorigenesis is now clearly established. However, how inflammation is elicited in the metastatic environment and the corresponding contribution of innate immunity pathways in suppressing tumor growth at secondary sites are poorly understood. Here, we show that mice deficient in Nlrp3 inflammasome components had exacerbated liver colorectal cancer metastatic growth, which was mediated by impaired inteleukin- 18 (IL-18) signaling. Control of tumor growth was independent of differential cancer cell colonization or proliferation, intestinal microbiota effects, or tumoricidal activity by the adaptive immune system. Instead, the inflammasome-IL-18 pathway impacted maturation of hepatic NK cells, surface expression of the death ligand FasL, and capacity to kill FasL-sensitive tumors. Our results define a regulatory signaling circuit within the innate immune system linking inflammasome activation to effective NK-cell-mediated tumor attack required to suppress colorectal cancer growth in the liver.