Center for Medical Ethics and Health Policy Staff Publications
Publication Date
12-3-2024
Journal
Cancer Immunology Research
DOI
10.1158/2326-6066.CIR-24-0469
PMID
39269772
PMCID
PMC11614694
PubMedCentral® Posted Date
6-3-2025
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Animals, Gastrointestinal Microbiome, Tumor Microenvironment, Lung Neoplasms, Mice, Humans, Inflammation, Adenocarcinoma of Lung, Lipocalin-2, Mice, Inbred C57BL, Disease Models, Animal, Fecal Microbiota Transplantation, Mice, Knockout
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.