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Cell. 2019 Feb 21;176(5):998-1013.e16. doi: 10.1016/j.cell.2018.12.040. Epub 2019 Jan 31.

Commensal Microbiota Promote Lung Cancer Development via γδ T Cells.

Author information

1
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
2
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3
Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
4
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.
5
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
6
Department of Medicine, Division of Computational Biomedicine, Boston University School of Medicine, Boston, MA 02118, USA.
7
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
8
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.
9
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
10
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. Electronic address: tjacks@mit.edu.

Abstract

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.

KEYWORDS:

IL-17; inflammation; lung adenocarcinoma; lung cancer; microbiota; neutrophils; tumor microenvironment; γδ T cells

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PMID:
30712876
PMCID:
PMC6691977
[Available on 2020-02-21]
DOI:
10.1016/j.cell.2018.12.040

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