Murine fecal microbiota transfer models selectively colonize human microbes and reveal transcriptional programs associated with response to neoadjuvant checkpoint inhibitors
Open accessAbstract
Human gut microbial species found to associate with clinical responses to immune checkpoint inhibitors (ICIs) are often tested in mice using fecal microbiota transfer (FMT), wherein tumor responses in recipient mice may recapitulate human responses to ICI treatment. However, many FMT studies have reported only limited methodological description, details of murine cohorts, and statistical methods. To investigate the reproducibility and robustness of gut microbial species that impact ICI responses, we performed human to germ-free mouse FMT using fecal samples from patients with non-small cell lung cancer who had a pathological response or nonresponse after neoadjuvant ICI treatment. R-FMT mice yielded greater anti-tumor responses in combination with anti-PD-L1 treatment compared to NR-FMT, although the magnitude varied depending on mouse cell line, sex, and individual experiment. Detailed investigation of post-FMT mouse microbiota using 16S rRNA amplicon sequencing, with models to classify and correct for biological variables, revealed a shared presence of the most highly abundant taxa between the human inocula and mice, though low abundance human taxa colonized mice more variably after FMT. Multiple Clostridium species also correlated with tumor outcome in individual anti-PD-L1-treated R-FMT mice. RNAseq analysis revealed differential expression of T and NK cell-related pathways in responding tumors, irrespective of FMT source, with enrichment of these cell types confirmed by immunohistochemistry. This study identifies several human gut microbial species that may play a role in clinical responses to ICIs and suggests attention to biological variables is needed to improve reproducibility and limit variability across experimental murine cohorts.
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Mouse models provide evidence that gut microbiota modifications from FMT improve ICI response, but magnitude depends on mouse strain or provider, sex, and experimental conditions.
“Studies in mouse models have provided compelling evidence that gut microbiota modifications resulting from faecal microbiota transplantation (FMT) improve ICI response rates38,42,91; however, the magnitude of these antitumour responses depends of factors such as the mouse strain or provider, mouse sex and individual experimental conditions106.”
From Gut OncoMicrobiome Signatures (GOMS) as next-generation biomarkers for cancer immunotherapy (2023) · cites this paper as [106]
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Gut OncoMicrobiome Signatures (GOMS) as next-generation biomarkers for cancer immunotherapy
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- Authors
- Shaikh, F. Y., Gills, J. J., Mohammad, F., White, J. R., Stevens, C. M., Ding, H., Fu, J., Tam, A., Blosser, R. L., Domingue, J. C., Larman, T. C., Chaft, J. E., Spicer, J. D., Reuss, J. E., Naidoo, J., Forde, P. M., Ganguly, S., Housseau, F., Pardoll, D. M., & Sears, C. L.
- Affiliations
- Johns Hopkins University (US)
- Resphera Biosciences (US)
- Memorial Sloan Kettering Cancer Center (US)
- McGill University (CA)
- Royal College of Surgeons in Ireland (IE)
- Corresponding author
- Sears, Cynthia L.
- ORCID
- Venue
- Cancer Immunology, Immunotherapy
- Published
- 2022-02-26
- Volume
- 71
- Issue
- 10
- Pages
- 2405-2420
- ISSN
- 0340-7004 (ISSN-L)
- 1432-0851
- PMC
- PMC9411268
- OpenAlex
- W4214496408
- Cited by
- 30
- References
- 38
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 9 · 2023: 6 · 2022: 1
- FWCI
- 2.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Immunology Immunotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
- Bristol-Myers Squibb
- National Institutes of Health (T32CA009071, P30 CA006973)
- International Association for the Study of Lung Cancer
- Lung Cancer Foundation of America
- National Center for Advancing Translational Sciences (KL2TR001077)
- Institute for Clinical and Translational Research, University of Wisconsin, Madison
- LUNGevity Foundation
- ECOG-ACRIN
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- fecal microbiota transplantation, immune checkpoint inhibitors, neoadjuvant therapy, non-small cell lung cancer, PD-L1 blockade, Clostridium, gut microbiota, antitumor immunity, T cells, natural killer cells, germ-free mice, 16S rRNA gene sequencing, RNA sequencing
- MeSH terms
- Fecal Microbiota Transplantation, Animals, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, RNA, Ribosomal, 16S, Reproducibility of Results, Neoadjuvant Therapy, Mice
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