1. Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade.
- Author
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Ferrere G, Tidjani Alou M, Liu P, Goubet AG, Fidelle M, Kepp O, Durand S, Iebba V, Fluckiger A, Daillère R, Thelemaque C, Grajeda-Iglesias C, Alves Costa Silva C, Aprahamian F, Lefevre D, Zhao L, Ryffel B, Colomba E, Arnedos M, Drubay D, Rauber C, Raoult D, Asnicar F, Spector T, Segata N, Derosa L, Kroemer G, and Zitvogel L
- Subjects
- 3-Hydroxybutyric Acid administration & dosage, 3-Hydroxybutyric Acid metabolism, Animals, CTLA-4 Antigen antagonists & inhibitors, Cell Line, Tumor, Combined Modality Therapy, Female, Gastrointestinal Microbiome immunology, Humans, Immune Checkpoint Inhibitors administration & dosage, Ketone Bodies metabolism, Kidney Neoplasms diet therapy, Kidney Neoplasms drug therapy, Kidney Neoplasms immunology, Melanoma, Experimental diet therapy, Melanoma, Experimental drug therapy, Melanoma, Experimental immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Experimental immunology, Receptors, G-Protein-Coupled antagonists & inhibitors, Diet, Ketogenic, Ketone Bodies administration & dosage, Neoplasms, Experimental diet therapy, Neoplasms, Experimental drug therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
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.
- Published
- 2021
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