Faculty Bibliography

Non-small cell lung cancer (NSCLC) remains the most common cause for cancer-related mortality despite advances in treatment. Early detection is crucial for improving patient outcomes, yet current diagnostic and prognostic molecular biomarkers lack the sensitivity and specificity necessary to become clinically useful. Recent studies revealed that the lower airway microbiome play a role in NSCLC and that microbial signatures are associated with NSCLC development, progression, and prognosis, suggesting the potential for microbiome-based biomarkers for early diagnosis and risk stratification. Here we review recent advances in the role of the local and systemic microbiome in early-stage NSCLC. Primarily, several studies have identified specific microbial taxa associated with lung cancer suggesting novel insights into disease pathogenesis and progression. Integration of microbiome data with other 'omics' platforms, such as host transcriptomics and metabolomics, has the potential to enhance our understanding of microbial-host interactions and may provide more comprehensive biomarker signatures. While promising, challenges remain to the development of microbiome-based biomarkers such as those related to differences in samples utilized, sequencing methods, and data analysis. Here, we discuss such challenges as well as future directions for research needed to fulfil the promise of microbiome-based biomarkers for changing early detection and management strategies in NSCLC.

RATIONALE/BACKGROUND:Lower airway enrichment with oral commensals has been previously associated with grade 3 severe primary graft dysfunction (PGD) after lung transplantation (LT). We aimed to determine whether this dysbiotic signature is present across all PGD severity grades, including milder forms, and whether it is associated with a distinct host inflammatory endotype. METHODS:Lower airway samples from 96 LT recipients with varying degrees of PGD were used to evaluate the lung allograft microbiota via 16S rRNA gene sequencing. Bronchoalveolar lavage (BAL) cytokine concentrations and cell differential percentages were compared across PGD grades. In a subset of samples, we evaluated the lower airway host transcriptome using RNA sequencing methods. RESULTS:Differential analyses demonstrated lower airway enrichment with supraglottic-predominant taxa (SPT) in both moderate and severe PGD. Dirichlet Multinomial Mixtures (DMM) modeling identified two distinct microbial clusters. A greater percentage of subjects with moderate-severe PGD were identified within the dysbiotic cluster (C-SPT) than within the no PGD group (48 and 29%, respectively) though this difference did not reach statistical significance (p=0.06). PGD severity associated with increased BAL neutrophil concentration (p=0.03) and correlated with BAL concentrations of MCP-1/CCL2, IP-10/CXCL10, IL-10, and TNF-α (p<0.05). Furthermore, microbial signatures of dysbiosis correlated with neutrophils, MCP-1/CCL-2, IL-10, and TNF-α (p<0.05). C-SPT exhibited differential expression of TNF, SERPINE1 (PAI-1), MPO, and MMP1 genes and upregulation of MAPK pathways, suggesting that dysbiosis regulates host signaling to promote neutrophilic inflammation. CONCLUSIONS:Lower airway dysbiosis within the lung allograft is associated with a neutrophilic inflammatory endotype, an immune profile commonly recognized as the hallmark for PGD pathogenesis. This data highlights a putative role for lower airway microbial dysbiosis in the pathogenesis of this syndrome.