Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade

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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.

Authors

Gladys Ferrere, Maryam Tidjani Alou, Peng Liu, Anne-Gaëlle Goubet, Marine Fidelle, Oliver Kepp, Sylvère Durand, Valerio Iebba, Aurélie Fluckiger, Romain Daillère, Cassandra Thelemaque, Claudia Grajeda-Iglesias, Carolina Alves Costa Silva, Fanny Aprahamian, Déborah Lefevre, Liwei Zhao, Bernhard Ryffel, Emeline Colomba, Monica Arnedos, Damien Drubay, Conrad Rauber, Didier Raoult, Francesco Asnicar, Tim Spector, Nicola Segata, Lisa Derosa, Guido Kroemer, Laurence Zitvogel