Commensal Microbiota Promote Lung Cancer Development via γδ T Cells
Commensal Microbiota Promote Lung Cancer Development via γδ T Cells
复制标题
DOI：
10.1016/j.cell.2018.12.040
复制
发表时间：
2019-02-21
期刊：
影响因子：
64.5
通讯作者：
Jacks, Tyler
中科院分区：
文献类型：
--
作者：
Jin, Chengcheng;Lagoudas, Georgia K.;Jacks, Tyler
肺癌与慢性炎症密切相关，但炎症的原因和特异性免疫介质尚未完全阐明。肺是由多种细菌群落定殖的粘膜组织，并且肺癌患者中常见的肺部感染与临床结果相关。在这里，我们提供的证据表明，局部微生物群通过激活肺部驻留的γ δ T细胞引起与肺腺癌相关的炎症。无菌或无菌处理的小鼠显著保护免于Kras突变和p53丢失诱导的肺癌发展。从机制上讲，细菌刺激Myd 88依赖性IL-1 β和IL-23从骨髓细胞产生，诱导V γ 6（+）V δ 1（+）γ δ T细胞的增殖和活化，产生IL-17和其他效应分子，促进炎症和肿瘤细胞增殖。我们的发现清楚地将局部微生物群-免疫串扰与肺肿瘤发展联系起来，从而定义了可能作为肺癌干预有效靶点的关键细胞和分子介质。
Lung cancer is closely associated with chronic inflammation, but the causes of inflammation and the specific immune mediators have not been fully elucidated. The lung is a mucosal tissue colonized by a diverse bacterial community, and pulmonary infections commonly present in lung cancer patients are linked to clinical outcomes. Here, we provide evidence that local microbiota provoke inflammation associated with lung adenocarcinoma by activating lung-resident gamma delta T cells. Germ-free or antibiotic-treated mice were significantly protected from lung cancer development induced by Kras mutation and p53 loss. Mechanistically, commensal bacteria stimulated Myd88-dependent IL-1 beta and IL-23 production from myeloid cells, inducing proliferation and activation of V gamma 6(+)V delta 1(+) gamma delta T cells that produced IL-17 and other effector molecules to promote inflammation and tumor cell proliferation. Our findings clearly link local microbiota-immune crosstalk to lung tumor development and thereby define key cellular and molecular mediators that may serve as effective targets in lung cancer intervention.