Journal
SCIENCE
Volume 369, Issue 6510, Pages 1481-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abc3421
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Funding
- Early Postdoc Mobility Fellowship from the Swiss National Science Foundation
- Canadian Institutes of Health Research (CIHR) [PJT-165930]
- Canadian Foundation for Innovation (CFI) John R. Evans Leaders Fund (JELF) grant
- Cumming School of Medicine
- Carole May Yates Memorial Endowment for Cancer Research
- CIHR [PJT-156073]
- CFI-JELF [34986]
- International Microbiome Centre (IMC)
- Canada Graduate Scholarship from the Natural Sciences and Engineering Research Council of Canada (NSERC)
- Alberta Innovates Translational Health Chair
- CIHR grant
- Terry Fox Research Institute grant
- Cumming School of Medicine, University of Calgary
- Western Economic Diversification (WED)
- Alberta Economic Development and Trade (AEDT), Canada
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Several species of intestinal bacteria have been associated with enhanced efficacy of checkpoint blockade immunotherapy, but the underlying mechanisms by which the microbiome enhances antitumor immunity are unclear. In this study, we isolated three bacterial species-Bifidobacterium pseudolongum, Lactobacillus johnsonii, and Olsenella species-that significantly enhanced efficacy of immune checkpoint inhibitors in four mouse models of cancer. We found that intestinal B. pseudolongum modulated enhanced immunotherapy response through production of the metabolite inosine. Decreased gut barrier function induced by immunotherapy increased systemic translocation of inosine and activated antitumor T cells. The effect of inosine was dependent on T cell expression of the adenosine A2A receptor and required costimulation. Collectively, our study identifies a previously unknown microbial metabolite immune pathway activated by immunotherapy that may be exploited to develop microbial-based adjuvant therapies.
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