학술논문
Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade
Document Type
article
Author
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
Source
JCI Insight, Vol 6, Iss 2 (2021)
Subject
Language
English
ISSN
2379-3708
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.