Abstract
Inosine produced by the gut microbe Bifidobacterium pseudolongum enhanced anti-CTLA4′s efficacy.
Major Finding: Inosine produced by the gut microbe Bifidobacterium pseudolongum enhanced anti-CTLA4′s efficacy.
Concept: Adenosine 2A receptor, which binds inosine, was needed for inosine-induced Th1-cell differentiation.
Impact: This highlights the role of the microbiome in cancer therapy and suggests possible therapeutics.
Although there is evidence that the species that constitute the gut microbiome affect response to immune-checkpoint blockade (ICB), the underlying molecular mechanisms are not clear. Mager and colleagues identified bacterial species present in ICB-treated colorectal tumors in mice and then demonstrated that the presence of some of these species, particularly Bifidobacterium pseudolongum, enhanced the efficacy of ICB treatment in four mouse models without having any antitumor activity on their own. Further, the presence of B. pseudolongum in the gut, rather than inside tumors, was sufficient for this effect, implying that soluble factors produced by or in response to B. pseudolongum may be responsible for the synergy. Indeed, serum from mice treated with anti-CTLA4 and colonized with B. pseudolongum—but not a different bacterial species—had antitumor effects and was rich in the metabolite inosine, which was further demonstrated to be produced by B. pseudolongum. Even in the absence of a tumor, B. pseudolongum colonization plus anti-CTLA4 treatment increased splenic Th1-cell activation and effector function. In the presence of IFNγ, inosine promoted the differentiation of naïve T cells into Th1 cells in vitro, and this effect was abolished by pharmacologic inhibition of adenosine 2A receptor (A2AR), which is known to bind inosine. In mice, the synergistic antitumor effect of anti-CTLA4 treatment plus B. pseudolongum colonization was absent in tumors deficient in A2AR. Notably, oral or systemic administration of inosine promoted the efficacy of anti-CTLA4 even in the absence of B. pseudolongum colonization, and this effect was also absent in mice with A2AR-deficient tumors. Demonstrating the broader relevance of these findings, inosine also promoted ICB response in mouse models of intestinal cancer, bladder cancer, and melanoma. In summary, this work supports a role for bacterially produced inosine in ICB response in multiple malignancies, emphasizing the importance of the gut microbiota for cancer therapy and paving the way for potential new therapeutic options.
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