生酮饮食增强免疫检查点抑制剂的抗肿瘤效果 | 热心肠日报
Ketogenic diet and ketone bodies enhance the anticancer effects of PD1 blockade
生酮饮食及酮体增强阻断PD-1的抗癌效果
10.1172/jci.insight.145207
12-15, Article
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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 an 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 ICB-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.
First Authors:
Gladys Ferrere
Correspondence Authors:
Guido Kroemer,Laurence Zitvogel
All 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,Deborah 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