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Messaoudene, Meriem; Pidgeon, Reilly; Richard, Corentin; Ponce, Mayra; Diop, Khoudia; Benlaifaoui, Myriam; Nolin-Lapalme, Alexis; Cauchois, Florent; Malo, Julie; Belkaid, Wiam; Isnard, Stephane; Fradet, Yves; Dridi, Lharbi; Velin, Dominique; Oster, Paul; Raoult, Didier; Ghiringhelli, François; Boidot, Romain; Chevrier, Sandy; Kysela, David T.; Brun, Yves V.; Falcone, Emilia Liana; Pilon, Geneviève; Oñate, Florian Plaza; [...]

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

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  • Media type: E-Article
  • Title: A Natural Polyphenol Exerts Antitumor Activity and Circumvents Anti–PD-1 Resistance through Effects on the Gut Microbiota
  • Contributor: Messaoudene, Meriem; Pidgeon, Reilly; Richard, Corentin; Ponce, Mayra; Diop, Khoudia; Benlaifaoui, Myriam; Nolin-Lapalme, Alexis; Cauchois, Florent; Malo, Julie; Belkaid, Wiam; Isnard, Stephane; Fradet, Yves; Dridi, Lharbi; Velin, Dominique; Oster, Paul; Raoult, Didier; Ghiringhelli, François; Boidot, Romain; Chevrier, Sandy; Kysela, David T.; Brun, Yves V.; Falcone, Emilia Liana; Pilon, Geneviève; Oñate, Florian Plaza; [...]
  • Published: American Association for Cancer Research (AACR), 2022
  • Published in: Cancer Discovery, 12 (2022) 4, Seite 1070-1087
  • Language: English
  • DOI: 10.1158/2159-8290.cd-21-0808
  • ISSN: 2159-8274; 2159-8290
  • Origination:
  • Footnote:
  • Description: 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
  • Access State: Open Access