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

Authors:
  • MMMeriem Messaoudene
    Meriem Messaoudene
  • CRCorentin Richard
    Corentin Richard
  • MPMayra Ponce
    Mayra Ponce
  • KDKhoudia Diop
    Khoudia Diop
  • MBMyriam Benlaifaoui
    Myriam Benlaifaoui
  • FCFlorent Cauchois
    Florent Cauchois
  • JMJulie Malo
    Julie Malo
  • WBWiam Belkaid
    Wiam Belkaid
  • SIStephane Isnard
    Stephane Isnard
  • YFYves Fradet
    Yves Fradet
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Abstract
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; Myrciaria dubia) 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 (Ruminococcaceae and Alistipes) and improved the CD8+/FOXP3+CD4+ 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 Ruminococcus bromii and promoted an anticancer response. Altogether, our results identify castalagin as a polyphenol that acts as a prebiotic to circumvent anti–PD-1 resistance.Significance: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.This article is highlighted in the In This Issue feature, p. 873