Data from A Natural Polyphenol Exerts Antitumor Activity and Circumvents Anti–PD-1 Resistance through Effects on the Gut Microbiota

Abstract

<div>Abstract<p>Several approaches to manipulate the gut microbiome for improving the activity of cancer immune-checkpoint inhibitors (ICI) are currently under evaluation. Here, we show that oral supplementation with the polyphenol-rich berry camu-camu (CC; <i>Myrciaria dubia</i>) in mice shifted gut microbial composition, which translated into antitumor activity and a stronger anti–PD-1 response. We identified castalagin, an ellagitannin, as the active compound in CC. Oral administration of castalagin enriched for bacteria associated with efficient immunotherapeutic responses (<i>Ruminococcaceae</i> and <i>Alistipes</i>) and improved the CD8<sup>+</sup>/FOXP3<sup>+</sup>CD4<sup>+</sup> ratio within the tumor microenvironment. Moreover, castalagin induced metabolic changes, resulting in an increase in taurine-conjugated bile acids. Oral supplementation of castalagin following fecal microbiota transplantation from ICI-refractory patients into mice supported anti–PD-1 activity. Finally, we found that castalagin binds to <i>Ruminococcus bromii</i> and promoted an anticancer response. Altogether, our results identify castalagin as a polyphenol that acts as a prebiotic to circumvent anti–PD-1 resistance.</p>Significance:<p>The polyphenol castalagin isolated from a berry has an antitumor effect through direct interactions with commensal bacteria, thus reprogramming the tumor microenvironment. In addition, in preclinical ICI-resistant models, castalagin reestablishes the efficacy of anti–PD-1. Together, these results provide a strong biological rationale to test castalagin as part of a clinical trial.</p><p><i>This article is highlighted in the In This Issue feature, p. 873</i></p></div>