A Natural Polyphenol Exerts Antitumor Activity and Circumvents Anti–PD-1 Resistance through Effects on the Gut Microbiota
Meriem Messaoudene, Reilly Pidgeon, Corentin Richard, Mayra Ponce, Khoudia Diop, Myriam Benlaïfaoui, Alexis Nolin-Lapalme, Florent Cauchois, Julie Malo, Wiam Belkaïd, Stéphane Isnard, Yves Fradet, Lharbi Dridi, Dominique Velin, P Oster, Didier Raoult, François Ghiringhelli, Romain Boidot, Sandy Chevrier, David T. Kysela, Yves V. Brun, Emilia Liana Falcone, Geneviève Pilon, Florian Plaza Oñate, Oscar Gitton-Quent, Emmanuelle Le Chatelier, Sylvère Durand, Guido Kroemer, Arielle Elkrief, André Marette, Bastien Castagner, Bertrand Routy
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.