A new study by Tsay et al sheds light on the role the lung microbiome may play in lung cancer pathogenesis and prognosis. According to the study’s findings, enrichment of the lungs with oral commensal microbes was associated with advanced-stage disease, worse prognosis, and tumor progression. Changes to the lung microbiome could be used as a biomarker to predict prognosis or to stratify patients for treatment, according to the study authors. The study was published in Cancer Discovery.

According to the American Cancer Society, lung cancer is the leading cause of cancer death among both men and women in the United States. Each year, more people die of lung cancer than of colorectal, breast, and prostate cancers combined. This year, approximately 228,820 new cases of lung cancer will be diagnosed, and about 135,720 people will die from the disease. Although advancements in lung cancer treatment, including immunotherapy, have improved survival, the majority of patients eventually experience disease progression.

Study Methodology

Between 2013 and 2018, researchers recruited 148 patients with lung nodules from the New York University Lung Cancer Biomarker Center who underwent clinical bronchoscopy for diagnostic purposes. Lower airway brushes were obtained for research. After excluding 65 patients who did not meet the study criteria, the researchers analyzed the lung microbiomes of 83 untreated patients with lung cancer using samples obtained from diagnostic clinical bronchoscopies. The samples were analyzed to identify microbial composition and to determine which genes were expressed in lung tissue.

Eighty-nine percent of the patients had a diagnosis of non–small cell lung cancer, of which 65% had adenocarcinoma and 49% were diagnosed with stage IIIB–IV disease.

Study Results

The researchers found that the patients with advanced-stage lung cancer (stages IIIB–IV) had greater enrichment of oral commensals in the lung than patients with early-stage disease (stages I–IIIA). In addition, the enrichment of oral commensals in the lung was associated with decreased survival, even after adjusting for tumor stage. Poor prognosis was associated with the enrichment of Veillonella, Prevotella, and Streptococcus bacteria in the lung microbiome, and tumor progression was associated with the enrichment of Veillonella, Prevotella, Streptococcus, and Rothia bacteria.

In patients with early-stage disease, the researchers found that enrichment of Veillonella, Prevotella, and Streptococcus was associated with activation of the p53, PI3K/PTEN, ERK, and IL-6/IL-8 signaling pathways. A Veillonella strain, found to be enriched in patients with advanced-stage lung cancer, was associated with the expression of IL-17, cell adhesion molecules, cytokines, and growth factors, as well as with the activation of the TNF, PI3K-AKT, and JAK-STAT signaling pathways.

The researchers also examined the effects of the lung microbiome in a mouse model of lung cancer. They seeded Veillonella parvula in the lungs of mice with lung cancer to model the enrichment of oral commensals. They found that it led to decreased survival, weight loss, and increased tumor burden. It was also associated with increased expression of IL-17 and other inflammatory proteins, increased recruitment of immune-suppressing cells, and increased activation of inflammatory pathways. To understand the role of IL-17 in lung cancer pathogenesis, the researchers treated Veillonella parvula–enriched mice with an antibody targeted to IL-17, which resulted in a significant decrease in tumor burden compared to mice treated with a control.

“This study has broad clinical implications regarding lung cancer pathogenesis and treatment response. Identification of lower airway dysbiotic signatures associated with lung cancer prognosis may be important to personalize approaches for lung cancer treatment and prognosis,” concluded the study authors.

Clinical Relevance

“Given the results of our study, it is possible that changes to the lung microbiome could be used as a biomarker to predict prognosis or to stratify patients for treatment, said senior study author Leopoldo N. Segal, MD, Director of the Lung Microbiome Program and Associate Professor of Medicine at the New York University Grossman School of Medicine, in a statement. “Another exciting possibility is to target the microbiome itself or the host response to microbes as a form of cancer therapy. Our results using an antibody against IL-17 suggest that this could be an effective strategy.”

Disclosure: Funding for this study was provided by the National Institutes of Health, the Department of Defense, the 2018 AACR-Johnson & Johnson Lung Cancer Innovation Science Grant, A Breath of Hope Lung Foundation, Simons Foundation, Clinical and Translational Science Awards, the Cancer Center Support Grant at the Laura and Isaac Perlmutter Cancer Center, the Flight Attendant Medical Research Institute Young Clinical Scientist Award, and the Stony Wold-Herbert Fund Grant-in-Aid/Fellowship. For full disclosures of the study authors, visit cancerdiscovery.aacrjournals.org.