Commensal Microbiota Promote Lung Cancer Development via γδ T Cells.,Cell

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Commensal Microbiota Promote Lung Cancer Development via γδ T Cells.
Cell ( IF 45.5 ) Pub Date : 2019-01-31 , DOI: 10.1016/j.cell.2018.12.040
Chengcheng Jin ₁ , Georgia K Lagoudas ₂ , Chen Zhao ₃ , Susan Bullman ₄ , Arjun Bhutkar ₁ , Bo Hu ₅ , Samuel Ameh ₁ , Demi Sandel ₁ , Xu Sue Liang ₁ , Sarah Mazzilli ₆ , Mark T Whary ₇ , Matthew Meyerson ₄ , Ronald Germain ₃ , Paul C Blainey ₈ , James G Fox ₉ , Tyler Jacks ₁₀

Affiliation

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, MA 02118, USA.
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

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 γδ 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-1β and IL-23 production from myeloid cells, inducing proliferation and activation of Vγ6+Vδ1+ γδ 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.

中文翻译：

共生菌群通过γδT细胞促进肺癌的发展。

肺癌与慢性炎症密切相关，但炎症的原因和特定的免疫介质尚未得到充分阐明。肺是由多种细菌群落定居的粘膜组织，肺癌患者中常见的肺部感染与临床结局有关。在这里，我们提供的证据表明，局部微生物群通过激活驻留于肺的γδT细胞引发了与肺腺癌相关的炎症。无胚芽或经抗生素治疗的小鼠受到了Kras突变和p53缺失诱导的肺癌发展的显着保护。从机理上讲，共生细菌刺激了髓样细胞对Myd88依赖性IL-1β和IL-23的产生，诱导产生IL-17和其他效应分子的Vγ6+Vδ1+γδT细胞的增殖和活化，从而促进炎症和肿瘤细胞的增殖。我们的发现清楚地将局部微生物群免疫串扰与肺癌的发生联系起来，从而确定了可能作为肺癌干预有效靶点的关键细胞和分子介质。

更新日期：2019-01-31

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