Journal
JCI INSIGHT
Volume 6, Issue 2, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.145207
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Funding
- Seerave Foundation
- Ligue contre le Cancer (equipe labellisee)
- Agence Nationale de la Recherche (ANR) -Projets blancs
- ANR
- ERA-Net for Research on Rare Diseases
- Association pour la recherche sur le cancer (ARC)
- Canceropole Ile-de-France
- Chancellerie des Universites de Paris
- Fondation pour la Recherche Medicale (FRM)
- European Commission
- European Research Council (ERC)
- Fondation Carrefour
- High-end Foreign Expert Program in China [GDW20171100085, GDW20181100051]
- Institut National du Cancer (INCa)
- Inserm (HTE)
- Institut Universitaire de France
- LeDucq Foundation
- LabEx Immuno-Oncology
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- CARE network
- (Kremlin Bicetre AP-HP)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- RHU Torino Lumiere [ANR-16-RHUS-0008]
- CNRS of Orleans (France)
- European funding in Region Centre-Val de Loire (FEDER) [EX005756 BIO-TARGET II]
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Limited experimental evidence suggests a link between nutrition and cancer immunosurveillance. This study demonstrates that ketogenic diet induces an anti-tumor effect through 3HB-mediated T cell-mediated cancer immunosurveillance. 3HB prevents immune checkpoint inhibition and promotes the expansion of specific T cells, while KD also leads to compositional changes in gut microbiota.
Limited experimental evidence bridges nutrition and cancer immunosurveillance. Here, we show that ketogenic diet (KD) - or its principal ketone body, 3-hydroxybutyrate (3HB), most specifically in intermittent scheduling - induced T cell-dependent tumor growth retardation of aggressive tumor models. In conditions in which anti-PD-1 alone or in combination with anti-CTLA-4 failed to reduce tumor growth in mice receiving a standard diet, KD, or oral supplementation of 3HB reestablished therapeutic responses. Supplementation of KD with sucrose (which breaks ketogenesis, abolishing 3HB production) or with a pharmacological antagonist of the 3HB receptor GPR109A abolished the antitumor effects. Mechanistically, 3HB prevented the immune checkpoint blockade-linked upregulation of PD-L1 on myeloid cells, while favoring the expansion of CXCR3(+) T cells. KD induced compositional changes of the gut microbiota, with distinct species such as Eisenbergiella massiliensis commonly emerging in mice and humans subjected to carbohydrate-low diet interventions and highly correlating with serum concentrations of 3HB. Altogether, these results demonstrate that KD induces a 3HB-mediated antineoplastic effect that relies on T cell-mediated cancer immunosurveillance.
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