Lung Microbiota Promote Lung Cancer

Although most patients with lung cancer suffer from lung infections at some point, the relationship between the lung microbiome and oncogenesis has remained unclear. Recently, however, a study demonstrated that, in mice predisposed to lung cancer, bacteria in the lung create a proinflammatory environment that promotes tumor growth (Cell 2019;176:998–1013).

“Coupled with data from human lung cancer, our work in the mouse strongly implicates bacteria as contributing to disease development,” says Tyler Jacks, PhD, of the Massachusetts Institute of Technology in Cambridge, senior author of the article.

The study was conducted in mice engineered to rapidly develop lung adenocarcinomas because they express an oncogenic form of Kras and lack the tumor suppressor Trp53. The researchers compared mice housed under normal conditions with mice living in a germ-free environment; the germ-free mice developed fewer and smaller tumors. They also noticed that in the mice kept under normal conditions, the diversity of the bacteria decreased even as the overall population of lung bacteria grew. This led them to hypothesize that tumors may have obstructed the airways, interfering with clearance of microbes and allowing new taxa to dominate.

Also, γδ T cells, which produce IL17, began to proliferate in the animals' lungs, contributing to a proinflammatory environment, further aided by the expansion of neutrophils.

To test the hypothesis that lung bacteria were boosting tumor growth, the researchers allowed another cohort of mice to develop tumors for several weeks. They then treated the mice with a cocktail of antibiotics and found that the expansion of γδ T cells was inhibited, as was tumor development. Treating the mice with drugs that blocked the action of γδ T cells or IL17 also impaired tumor development. In a separate experiment, when researchers transferred bacteria collected from mouse tumors to the lungs of another cohort of mice just beginning to develop tumors, their tumor burden 8 weeks later was nearly double that of mice that did not receive the bacterial transfer.

Finally, when the researchers compared human cancerous and healthy lung tissue, they found significant enrichment or depletion of various bacterial taxa, as well as significant infiltration of γδ T cells, in the tumors—similar to what they saw in mice.

Curtis Harris, MD, of the NCI, who was not involved in this study, says that these findings complement those of a study conducted by his lab, which documented differences in the microbiota of patients with lung cancer versus those without the disease (Genome Biology 2018;19:123).

Harris adds that he would like to see whether the results can be replicated in other mouse models. “The findings would be strengthened by expanding to squamous cell carcinoma and small cell carcinoma models, as well as tobacco smoke–induced models,” he says.

In the meantime, Jacks and colleagues are using their mouse model to identify drugs that can prevent bacteria from establishing a proinflammatory environment—and to learn which bacteria are most strongly associated with lung tumors.

“It is possible,” says Jacks, “that interfering with the pathways involved could slow the course of lung cancer development, with an emphasis on disease interception as opposed to disease treatment.” –Kristin Harper

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