JCI Insight (Jan 2021)

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

  • 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

Journal volume & issue
Vol. 6, no. 2

Abstract

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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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