Airway Fusobacterium is Associated with Poor Response to Immunotherapy in Lung Cancer

Abstract

There is a major limitation in the immunotherapy for solid cancer is that it only benefited a minority of cancer patients. This study aims to investigate whether the differential composition of the lung microbiome could affect the sustained clinical responses in lung cancers treated with immunotherapy. Methods: Twenty-seven non-responders and 19 responders treated with anti-PD-1 therapy were included in the discovery set. Bacterial load in bronchoalveolar lavage from lung cancer patients was examined by quantitative PCR of 16S rRNA copies. Bacterial 16S rDNA was sequenced using the Illumina HiSeq on the 16S rDNA V3-V4 variable region. Operational taxonomic unit (OTU) analysis was performed using VSEARCH v2. The α-diversity and β-diversity were calculated using QIIME software. Results:The mean copy number of bacterial 16S DNA levels significantly decreased after anti-PD-1 treatment (after: 1.8 ± 0.6×10 4 copies per milliliter vs prior to treatment: 3.3 ± 1.1x10 4 , p = 0.0036). In addition, longitudinal analysis revealed that microbial diversity was reduced taxonomically after treatment compared to those prior to the treatment (Shannon values: before: 3.291 ± 0.067 vs after: 2.668 ± 0.168, p < 0.01). Further, we observed a reduction of Fusobacterium nucleatum, including phylum Fusobacteria (p < 0.01), class Fusobacteria (p < 0.01), order Fusobacteria (p < 0.01), family Fusobacteria (p < 0.01), genus Fusobacteria (p = 0.025) in the responders post anti-PD-1 treatment. However, there was no significant difference of Fusobacterium in non-responders. An independent cohort was used to validate the levels of Fusobacterium, demonstrating that patients with higher abundance of Fusobacterium prior to treatment were significantly more likely to have poor response to anti-PD-1 therapy (p < 0.001). Conclusion: Airway enriched Fusobacterium prior to anti-PD-1 therapy is associated with poor response in lung cancer, which indicated that potential resistance to immunotherapy can be attributed to lung microbiome.

Dual oxic-anoxic co-culture enables direct study of host-anaerobe interactions at the airway epithelial interface

“…Twenty-one other cancer-related genes varied by cell type (padj < 0.001). While F. nucleatum has been associated with late-stage lung cancer 56,57 and poor patient response to immunotherapy 58 , these data support a direct role for the bacterium in airway carcinogenesis. To our knowledge, these data are the first to reveal the epithelial response to bacterial challenge with the granularity afforded by scRNAseq and further demonstrate the power and versatility of the DOAC platform to model anaerobe-host interactions.…”

Involvement of Fusobacterium nucleatum in malignancies except for colorectal cancer: A literature review

“…CRC mice treated with radiotherapy combined with metronidazole had a significantly reduced tumor burden and radiation enteritis ( 101 ). High intratumoral F. nucleatum burden predicted a poor response to neoadjuvant chemotherapy in ESCC and airway enriched Fusobacterium prior to anti-PD-1 monotherapy was associated with resistance to immunotherapy in lung cancer ( 47 , 67 , 69 ). The mechanisms of how the antibiotics exerts the critical role in the carcinogenesis and antitumor effects in malignancies other than CRC need to be further explored.…”

“…The relationship between bacterial load and diversity with the clinical response to anti-PD-1 therapy was further analyzed. Airway enriched Fusobacterium prior to anti-PD-1 monotherapy was associated with resistance to anti-PD-1 response, providing potential implication in treatment resistance in the immunotherapy of lung cancer ( 69 ).…”

Periodontopathogens Porphyromonas gingivalis and Fusobacterium nucleatum and Their Roles in the Progression of Respiratory Diseases

“…This alignment between the antibody levels and lung cancer underscores a potential association between F. nucleatum and the pathogenesis of lung cancer, meriting further investigation. Chu et al [ 83 ] found that airway-enriched F. nucleatum before anti-PD-1 treatment was associated with resistance to anti-PD-1 response in lung cancer, suggesting F. nucleatum may not only be related to the development of lung cancer, but also increase the resistance of cancer tissue to immunotherapy. While some investigations have documented the detection of F. nucleatum within pleural effusions of lung cancer patients [ 84 ], specific evidence establishing a direct correlation between F. nucleatum and lung cancer remains relatively limited.…”