Journal
CANCER DISCOVERY
Volume 12, Issue 4, Pages 1070-1087Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-21-0808
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Funding
- Institut du Cancer de Montreal
- Canadian Institute for Health Research
- Fondation du CHUM
- Canada Research Chair in Therapeutic Chemistry
- Reseau de Therapie cellulaire, Tissulaire et Genique du Quebec (TheCell)
- Fonds de la Recherche Quebec-Sante (FRQ-S): Reseau SIDA/Maladies infectieuses, Therapie cellulaire
- Vaccines and Immunotherapies Core of the CIHR Canadian HIV Trials Network (CTN) [CTN 247]
- CIHR
- Fondation J.A. De Seve
- Pfizer research fund
- Fonds de recherche du Quebec-Sante (FRQS), FRQS junior I career awards
- FRQS postdoctoral research scholarship [303637]
- Seerave Foundation
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The study demonstrates that oral supplementation with polyphenol-rich berry camu-camu alters gut microbial composition in mice, leading to antitumor activity and enhanced anti-PD-1 response. The active compound castalagin enriches for specific bacteria and induces metabolic changes to support immunotherapy efficacy.
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; Myrciorio dubio) 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 (Ruminococcoceae 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.
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