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

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.

Very‐low‐carbohydrate diet enhances human T‐cell immunity through immunometabolic reprogramming

“…These new immunological aspects of KD might contribute to the modern concept of metabolic therapy of cancer (Seyfried et al , 2017 , 2020 ). KD not only targets the Warburg effect, but could also strengthen anti‐tumor immunity (Ferrere et al , 2021 ). Moreover, the different effects of BHB‐induced ROS elevation on tumor cells and T cells might even lead to additive beneficial effects: While oxidative stress compromises cancer cell viability, mild increase in ROS enhances T‐cell immune capacity which in turn further restrains tumor growth.…”

Fucoidan-Supplemented Diet Potentiates Immune Checkpoint Blockage by Enhancing Antitumor Immunity

“…Furthermore, protein restriction diet can synergize with immunotherapies through reprogramming the tumor associated macrophages ( Orillion et al, 2018 ). Oral supplementation with Akkermansia muciniphila and ketone bodies were reported to enhance the efficacy of PD-1 blockade ( Routy et al, 2018 ; Ferrere et al, 2021 ). Fucoidan in particular is a soluble dietary component that is considered functional food with health benefits ( Di Daniele et al, 2017 ).…”

Oral administration of Akkermansia muciniphila elevates systemic antiaging and anticancer metabolites

“…The ketone body 2-hydroxybutyrate can be administered to mice and stimulates anticancer immune responses in the context of immune checkpoint [52]. 2hydroxybutyrate is increased in the context of ketogenic diets, which are known for their antiaging effects [53][54][55], as well as their capacity to stimulate anticancer immunity [56].…”