Aims:
Lung cancer remains the leading cause of cancer-related mortality, yet the lung microbiome’s role in tumour biology is poorly defined. Here, we characterised the extra-tumoural lung microbiome in Australians with early- and late-stage lung cancer to determine associations with disease and demographic parameters.
Methods:
Matched oral washes, primary tumour bronchial washings (BWs), and contralateral BWs were prospectively collected from 106 lung cancer participants (51% early-stage, 49% late-stage) and 10 controls undergoing bronchoscopy. Specimens underwent host-depleted shotgun metagenomics and conventional culture. Microbial diversity and community structure were assessed using Shannon indices and Aitchison distance with PERMANOVA. Multivariable mixed-effects modelling was used to identify taxa associated with disease state, stage, spatial site, histological subtype, sex, and smoking pack-years.
Results:
Cumulative smoking exposure exerted the strongest influence on lung microbiome composition, driving core respiratory commensal depletion and Streptococcus mitis enrichment, independent of cancer histology. Adjusting for smoking, tumour presence dictated microbiome structure. Early-stage tumour BWs showed significantly lower α diversity (p=0.027 vs. healthy), and markedly reduced microbial cultivability (p<0.001) and significant respiratory commensal depletion (FDR q<0.05) compared with contralateral BWs. Paired spatial modelling revealed profound depletion of core oral and lung commensals, and pseudomonad enrichment, in tumour BWs. Late-stage tumour BWs exhibited depletion of three anaerobes. Matched oral microbiome analysis revealed that tumour BWs were uniquely enriched for distinct respiratory taxa. Filamentous fungal cultivability was significantly lower in tumour BWs (p<0.01). Notably, no significant taxonomic differences were observed across lung cancer subtypes.
Conclusions:
In this Australia-first study, smoking history and the tumour microenvironment emerged as dominant ecological pressures in the lung microbiome. Significant commensal collapse and selective enrichment of specific taxa at the extra-tumoural site indicate a profoundly altered lower airway microbiome in people with lung cancer. These findings highlight the need for ongoing research and development of microbiome-based biomarkers and therapies.