Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy

By L. Mager, R. Burkhard, Nicola Pett, Noah C. A. Cooke, Kirsty Brown, H. Ramay, Seungil Paik, J. Stagg, R. Groves, M. Gallo and 3 more. Science, 2020

1,157 citations recorded by the source corpus.

Inosine modulates antitumor immunity Checkpoint blockade immunotherapy harnesses the immune system to kill cancer cells and has been used with great success to treat certain tumors, but not all cancer patients respond. The efficacy of checkpoint blockade immunotherapy has been shown to depend on the presence of distinct, beneficial bacteria residing in the gut of patients, but how the microbiome mediates such beneficial effects is unclear. Mager et al. found that specific bacteria produce a metabolite called inosine that enhances the effect of checkpoint blockade immunotherapy (see the Perspective by Shaikh and Sears). In mouse models, inosine, together with proinflammatory stimuli and immunotherapy, strongly enhanced the antitumor capacities of T cells in multiple tumor types, including colorectal cancer, bladder cancer, and melanoma. Science, this issue p. 1481; see also p. 1427 The bacterial-derived metabolite inosine enhances cancer immunotherapy in mice. 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.

Subfields: Immunology, Oncology, Physiology

View Paper: https://www.semanticscholar.org/paper/041ece73120d89c36e2870fa3f1b95b4ebdafab2

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In Immunology

1. Rob Knight
2. L. Zitvogel
3. J. Wargo
4. D. Hanahan
5. Guido Kroemer
6. L. Galluzzi

In Oncology

1. L. Zitvogel
2. D. Hanahan
3. J. Wargo
4. Rakesh K. Jain
5. Guido Kroemer

In Physiology

1. Rob Knight
2. L. Zitvogel
3. D. Hanahan

Citations in the corpus

• The microbiome and human cancer (2021, background): “Anti–CTLA-4–induced gut barrier dysfunction was also critical for systemic translocation of Bifidobacterium-derived inosine, in turn promoting TH1 activation and antitumor immunity by agonizing T cell–specific adenosine 2A receptor (A2AR) signaling in the context of DC costimulation (93).”
• Hallmarks of Cancer: New Dimensions. (2022, background): “Other immunoregulatory molecules produced by specific bacterial subspecies are being identified and functionally evaluated, including bacteria-produced inosine, a rate-limiting metabolite for T-cell activity (100).”