Lower Airway Dysbiosis Affects Lung Cancer Progression
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Abstract
Abstract In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB–IV tumor–node–metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I–IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB–IV disease. In addition, this lower airway microbiota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers. Significance: Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis. See related commentary by Zitvogel and Kroemer, p. 224. This article is highlighted in the In This Issue feature, p. 211
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Increasing evidence supports an additional category of complicit microbes and microbial functions that promote carcinogenesis but are not sufficient to cause cancer.
“Increasing evidence suggests an important additional category of “complicit” microbes and microbial functions that promote carcinogenesis but are insufficient to cause cancer (18, 20, 25, 38, 44–47).”
From The microbiome and human cancer (2021) · cites this paper as [25]
Extra-intestinal cancers can develop within tissues that harbor their own microbiome, and that microbiome may play a role in exacerbating neoplasia.
“However, it is noteworthy that extra-intestinal cancers can develop within tissues that harbor their own microbiome and may play a role in the exacerbation of neoplasia (12, 18, 25, 46).”
From The microbiome and human cancer (2021) · cites this paper as [25]
In 83 lung cancer patients, microaspiration of supraglottic commensals can affect response to therapies and overall survival due to TH17-mediated exacerbated inflammation associated with immune checkpoint inhibition.
“Tsay et al. highlighted that microaspiration of supraglottic commensals in lung cancer patients can affect response to therapies and overall survival, due to a TH17-mediated exacerbated inflammation corollary to immune checkpoint inhibition (25).”
From The microbiome and human cancer (2021) · cites this paper as [25]
Some MGSs significantly associated with OS < 12 in the discovery cohort (e.g., Hungatella hathewayi, Clostridium innocuum, Streptococcus anginosus, Actinomyces graevenitzii) had been previously described in antibiotic-treated or poor prognosis cancer patients.
“Some of the MGSs that were significantly associated with OS < 12 were already described in antibiotic-treated or poor prognosis cancer patients (such as Hungatella hathewayi, Clostridium innocuum, Streptococcus anginosus, or Actinomyces graevenitzii).”
From Custom scoring based on ecological topology of gut microbiota associated with cancer immunotherapy outcome (2024) · cites this paper as Tsay et al., 2021
SIG1 comprises many microbial components of the oral cavity that can transit from the supraglottic compartment down to the bronchoalveolar space or the small intestine, as a result of pH fluctuations, comedications (proton pump inhibitors), or dysphagia.
“In fact, SIG1 comprises many microbial components of the oral cavity that can transit from the supraglottic compartment down to the bronchoalveolar space or the small intestine, as a result of pH fluctuations, comedications (proton pump inhibitors), or dysphagia.25”
From Custom scoring based on ecological topology of gut microbiota associated with cancer immunotherapy outcome (2024) · cites this paper as [32]
Veillonella spp. have the capacity to expand TH17 pro-angiogenic and pro-oncogenic lymphocytes that contribute to dismal prognosis and resistance to cytotoxicants in NSCLC.
“Veillonella spp. have the capacity to expand TH17 pro-angiogenic and pro-oncogenic lymphocytes that contribute to dismal prognosis and resistance to cytotoxicants in NSCLC.32”
From Custom scoring based on ecological topology of gut microbiota associated with cancer immunotherapy outcome (2024) · cites this paper as [32]
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The microbiome and human cancer
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Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions
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Microbiota-Centered Interventions: The Next Breakthrough in Immuno-Oncology?
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- Authors
- Tsay, J.-C. J., Wu, B. G., Sulaiman, I., Gershner, K., Schluger, R., Li, Y., Yie, T.-A., Meyn, P., Olsen, E., Perez, L., Franca, B., Carpenito, J., Iizumi, T., El-Ashmawy, M., Badri, M., Morton, J. T., Shen, N., He, L., Michaud, G., Rafeq, S., Bessich, J. L., Smith, R. L., Sauthoff, H., Felner, K., Pillai, R., Zavitsanou, A.-M., Koralov, S. B., Mezzano, V., Loomis, C. A., Moreira, A. L., Moore, W., Tsirigos, A., Heguy, A., Rom, W. N., Sterman, D. H., Pass, H. I., Clemente, J. C., Li, H., Bonneau, R., Wong, K.-K., Papagiannakopoulos, T., & Segal, L. N.
- Affiliations
- VA NY Harbor Healthcare System (US)
- New York University (US)
- Wake Forest University Health Sciences (US)
- Simons Foundation (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Segal, Leopoldo N.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2021-02-01
- Volume
- 11
- Issue
- 2
- Pages
- 293-307
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC7858243
- OpenAlex
- W3101608661
- Cited by
- 322
- References
- 92
- Citations by year
- 2026: 48 · 2025: 74 · 2024: 56 · 2023: 68 · 2022: 52 · 2021: 24
- FWCI
- 11.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH NCI (R37 CA244775)
- NIH NIAD (K23 AI102970)
- EDRN (5U01CA086137-13)
- DoD (W81XWH-16-1-0324)
- AACR–Johnson and Johnson Lung Cancer Innovation Science (18-90-52-ZHAN)
- CTSI (#UL1 TR000038)
- Genome Technology Center Cancer Center Support Laura and Isaac Perlmutter Cancer Center (P30CA016087)
- Laura and Isaac Perlmutter Cancer Center (T32 CA193111, UL1TR001445)
- NIH NHLBI (R01 HL125816, R01 DK110014)
- Cancer Center Support (P30CA016087)
- Vectra (S10 OD021747)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- lung cancer, lower airway microbiota, dysbiosis, Veillonella parvula, oral commensals, tumor progression, prognosis, survival, PI3K signaling, MAPK signaling, ERK signaling, airway transcriptome, immune checkpoint inhibitors, immunotherapy response, carcinogenesis
- MeSH terms
- Adenocarcinoma, Animals, Disease Models, Animal, Female, Humans, Lung Neoplasms, Mice, Transgenic, Neoplasm Metastasis, Neoplasm Staging, New York, Cohort Studies, Proportional Hazards Models, Survival Analysis, Disease Progression, Mice, Microbiota, Dysbiosis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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