Commensal Microbiota Promote Lung Tumorigenesis via ?d T Cells

Lung cancer is closely associated with chronic inflammation, but the mechanism underlying such inflammation has not been clearly defined. The lung is a mucosal tissue colonized by a diverse bacterial community at the steady state, 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 tumor initiation and progression induced by Kras mutation and p53 loss. Mechanistically, commensal bacteria stimulated My88-dependent IL-1beta and IL-23 production from myeloid cells, inducing proliferation and activation of V?6+Vd1+ ?d T cells that produced IL-17 and other effector molecules to promote inflammation and tumor cell proliferation. Our findings provide a clear link between local microbiota-immune crosstalk and lung tumorigenesis, and thereby define key cellular and molecular mediators that may serve as effective targets in lung cancer treatment and prevention. Overall design: ?dT cells were isolated from tumor-bearing lungs or spleens of KP mice. Their transcriptional profiles are compared with RNA-seq.

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Jin C, Lagoudas GK, Zhao C, Bullman S, Bhutkar A, Hu B, Ameh S, Sandel D, Liang XS, Mazzilli S, Whary MT, Meyerson M, Germain R, Blainey PC, Fox JG, Jacks T