Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy

TLDR

Several species of intestinal bacteria have been linked to improved efficacy of checkpoint blockade immunotherapy, yet the mechanisms by which the microbiome enhances antitumor immunity remain unclear. The study isolated three bacterial species—Bifidobacterium pseudolongum, Lactobacillus johnsonii, and Olsenella species—that significantly boosted immune checkpoint inhibitor efficacy in four mouse cancer models. The authors tested these isolates in the mouse models to evaluate their impact on checkpoint therapy, thereby establishing a mechanistic link between specific gut microbes and antitumor response. They found that B.

Abstract

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.