Editors' ChoiceCancer

Don’t overlook the lung

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Science Translational Medicine  20 Feb 2019:
Vol. 11, Issue 480, eaaw5330
DOI: 10.1126/scitranslmed.aaw5330

Abstract

The local lung microbiota provoke inflammation associated with lung adenocarcinoma by activating lung-resident γδ T cells in mice.

Recent studies have elegantly described how the gut microbiota affects immunotherapy responsiveness in certain cancers. Those studies showed how the gut microbiome affects host immunity leading to distant therapeutic effects from where the microbial-host interaction occurs. The lung has been somewhat neglected as another possible source of microbiota-host interaction, despite being the human mucosae with the largest surface area exposed to the external world. However, this is now the focus of a study by Jin et al., which demonstrated that the lower airway microbiota contributes to a protumor environment in lung cancer. Using a genetically engineered mouse model of lung adenocarcinoma (KrasLSL-G12D; p53flox/flox, termed KP), the authors demonstrated that tumor development was blunted under germ-free conditions as compared with specific pathogen-free conditions. Similar results were found when using an antibiotic cocktail. Lung cancer microbiota was associated with increased production of interleukin-1β (IL-1β), IL-23, and a higher number of IL-17–producing γδ T cells, which led to neutrophil infiltration in tumor-bearing lungs. Importantly, γδ T cells of tumor-bearing KP mice had increased IL-22, and blocking this cytokine decreased tumor burden.

The authors then extended their investigations to human samples where they observed increased infiltration of γδ T cells by immunohistochemistry in a subset of samples from subjects with lung cancer as compared with controls. Further, patients with elevated IL-22 had worse survival, suggesting that the inflammatory signatures associated with lung cancer microbiota have significant effects on the natural history of the disease. These findings suggest that targeting the microbiota may stymie lung cancer development. However, germ-free models (or even the antibiotic cocktail model) are unlikely to represent any microbial condition achievable in adult humans. Also, the lower airway microbiota of humans is quite different from the lung microbiota in mice. The effects of the lower airway microbiota on immunotherapy—for example, programmed cell death 1 blockade—were not evaluated and will likely be the focus of future investigations. Thus, the time for debunking the misconception that the lungs are sterile is passing. We now need to face the challenge of dissecting the mechanism by with distinct microbial functions affect the lung immunological environment, a pursuit that may have important implications in lung cancer.

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