Inflammation Mediated by Gut Microbiome Alterations Promotes Lung Cancer Development and an Immunosuppressed Tumor Microenvironment

Accumulating evidence indicates that the gut microbiome influences cancer progression and therapy. We recently showed that progressive changes in gut microbial diversity and composition are closely coupled with tobacco-associated lung adenocarcinoma in a human-relevant mouse model. Furthermore, we demonstrated that the loss of the antimicrobial protein Lcn2 in these mice exacerbates protumor inflammatory phenotypes while further reducing microbial diversity. Yet, how gut microbiome alterations impinge on lung adenocarcinoma development remains poorly understood. In this study, we investigated the role of gut microbiome changes in lung adenocarcinoma development using fecal microbiota transfer and delineated a pathway by which gut microbiome alterations incurred by loss of Lcn2 fostered the proliferation of proinflammatory bacteria of the genus Alistipes, triggering gut inflammation. This inflammation propagated systemically, exerting immunosuppression within the tumor microenvironment, augmenting tumor growth through an IL6-dependent mechanism and dampening response to immunotherapy. Corroborating our preclinical findings, we found that patients with lung adenocarcinoma with a higher relative abundance of Alistipes species in the gut showed diminished response to neoadjuvant immunotherapy. These insights reveal the role of microbiome-induced inflammation in lung adenocarcinoma and present new potential targets for interception and therapy.

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Publication Details

Journal
Cancer Immunology Research
Published
2024-09-13
DOI
https://doi.org/10.1158/2326-6066.cir-24-0469
Citations
21
Primary Topic
Gut microbiota and health
Type
article
Field-Weighted Citation Impact
4.91

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article

Inflammation Mediated by Gut Microbiome Alterations Promotes Lung Cancer Development and an Immunosuppressed Tumor Microenvironment

Cheuk Hong Leung, Tieling Zhou, Inti Tarifa Reischle, Don L. Gibbons et al.
21 citations
Cancer Immunology Research
Gut microbiota and health
4.91
article

Inflammation Mediated by Gut Microbiome Alterations Promotes Lung Cancer Development and an Immunosuppressed Tumor Microenvironment

Cheuk Hong Leung, Tieling Zhou, Inti Tarifa Reischle, Don L. Gibbons, Yuejiang Liu, Seyed Javad Moghaddam, Nadim J. Ajami, Matthew C. Wong, Robert R. Jenq, Joseph F. Petrosino, Elizabeth Tang, Fuduan Peng, Jennifer Ann Wargo, Ansam Sinjab, Zahraa Rahal, Minyue Chen, Humam Kadara, Linghua Wang, Jiping Feng, Hannah Moreno, Camille Abaya, Boris Sepesi, Nathaniel Deboever, Matthew C. Ross, Tina Cascone, Mohamed A. Jamal, Manvi Sharma, Ashish Damania, Heather Yan Lin, Kristi L. Hoffman, Junya Fujimoto, Chidera Chukwuocha, J. Jack Lee, Sujuan Yang, Jamie K. Lim
article en
21 citations

Abstract

Accumulating evidence indicates that the gut microbiome influences cancer progression and therapy. We recently showed that progressive changes in gut microbial diversity and composition are closely coupled with tobacco-associated lung adenocarcinoma in a human-relevant mouse model. Furthermore, we demonstrated that the loss of the antimicrobial protein Lcn2 in these mice exacerbates protumor inflammatory phenotypes while further reducing microbial diversity. Yet, how gut microbiome alterations impinge on lung adenocarcinoma development remains poorly understood. In this study, we investigated the role of gut microbiome changes in lung adenocarcinoma development using fecal microbiota transfer and delineated a pathway by which gut microbiome alterations incurred by loss of Lcn2 fostered the proliferation of proinflammatory bacteria of the genus Alistipes, triggering gut inflammation. This inflammation propagated systemically, exerting immunosuppression within the tumor microenvironment, augmenting tumor growth through an IL6-dependent mechanism and dampening response to immunotherapy. Corroborating our preclinical findings, we found that patients with lung adenocarcinoma with a higher relative abundance of Alistipes species in the gut showed diminished response to neoadjuvant immunotherapy. These insights reveal the role of microbiome-induced inflammation in lung adenocarcinoma and present new potential targets for interception and therapy.

Cancer Immunology ResearchVol. 12(12)
The University of Texas MD Anderson Cancer Center (US), Johns Hopkins University (US), University of Illinois Urbana-Champaign (US), Baylor College of Medicine (US), Johns Hopkins Medicine (US), Hiroshima University Hospital (JP), The University of Texas Health Science Center (US), Trinity University (US)
Bristol-Myers Squibb, National Institutes of Health, University of Texas MD Anderson Cancer Center, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 4%
Gut microbiota and health
4.91
DOIOpen Access PDFOpenAlex
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