A Natural Polyphenol Exerts Antitumor Activity and Circumvents Anti-PD-1 Resistance through Effects on the Gut Microbiota PMID: 35031549

ADC Targets in Oncology

2026-04-10

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

Cancer Discov. 2022 Apr 1;12(4):1070-1087. doi: 10.1158/2159-8290.CD-21-0808.

Meriem Messaoudene ¹ , Reilly Pidgeon ² , Corentin Richard ¹ , Mayra Ponce ¹ , Khoudia Diop ¹ , Myriam Benlaifaoui ¹ , Alexis Nolin-Lapalme ¹ , Florent Cauchois ¹ , Julie Malo ¹ , Wiam Belkaid ¹ , Stephane Isnard ³ , Yves Fradet ⁴ , Lharbi Dridi ² , Dominique Velin ⁵ , Paul Oster ⁵ , Didier Raoult ⁶ , François Ghiringhelli ⁷ , Romain Boidot ⁸ ⁹ , Sandy Chevrier ⁸ , David T Kysela ¹⁰ , Yves V Brun ¹⁰ , Emilia Liana Falcone ¹¹ ¹² , Geneviève Pilon ¹³ , Florian Plaza Oñate ¹⁴ , Oscar Gitton-Quent ¹⁴ , Emmanuelle Le Chatelier ¹⁴ , Sylvere Durand ¹⁵ ¹⁶ , Guido Kroemer ¹⁵ ¹⁶ ¹⁷ , Arielle Elkrief ¹ , André Marette ¹³ , Bastien Castagner ² , Bertrand Routy ¹ ¹⁸

Affiliations

1. University of Montreal Hospital Research Centre (CRCHUM), Montreal, Quebec, Canada.
2. Department of Pharmacology and Therapeutics, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada.
3. Research Institute, McGill University Health Centre, Montreal, Quebec, Canada.
4. Centre de recherche du CHU de Québec, Oncology Division, CHU de Québec, Université Laval, Québec City, Quebec, Canada.
5. Service of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
6. Aix Marseille Université, IRD, AP-HM, MEPHI, IHU-Méditerranée Infection, Marseille, France.
7. Department of Medical Oncology, Center GF Leclerc, Dijon, France.
8. Unit of Molecular Biology, Department of Biology and Pathology of Tumors, Georges-François Leclerc Cancer Center, UNICANCER, Dijon, France.
9. UMR CNRS 6302, Dijon, France.
10. Faculté de Médecine, Département de Microbiologie, Infectiologie et Immunologie, University of Montreal, Montreal, Quebec, Canada.
11. Department of Immunity and Viral Infections, Montreal Clinical Research Institute (IRCM), Montreal, Quebec, Canada.
12. Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
13. Department of Medicine, Faculty of Medicine, Cardiology Axis of the Québec Heart and Lung Institute and Institute of Nutrition and Functional Foods, Laval University, Québec City, Quebec, Canada.
14. Université Paris-Saclay, INRAE, MGP, Jouy-en-Josas, France.
15. Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
16. Centre de Recherche des Cordeliers, Équipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France.
17. Pôle de Biologie, Hôpital Européen Georges Pompidou, Paris, France.
18. Hematology-Oncology Division, Department of Medicine, University of Montreal Healthcare Centre (CHUM), Montreal, Quebec, Canada.

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.