Journal Article

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

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

2021

Overview

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.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Antitumor activity / Bioenergetics / Cancer / Carbohydrates / Chronic illnesses / CTLA-4 protein / Cultural heritage / CXCR3 protein / Diet / Dietary supplements / Growth rate / High fat diet / Immune checkpoint inhibitors / Immune response / Immune system / Immunosurveillance / Immunotherapy / Intestinal microflora / Ketogenesis / Ketones / Kinases / Low carbohydrate diet / Lymphocytes T / Melanoma / Metabolism / Metabolites / Microbiota / Myeloid cells / Nutrient deficiency / Oncology / PD-1 protein / PD-L1 protein / Polyamines / Proteins / Sucrose / Tumors