生酮饮食或能增强癌症免疫治疗
创作:szx 审核:szx 2020年12月28日
  • 生酮饮食通过产生3HB,以T细胞依赖性方式抑制小鼠的肿瘤进展;
  • 生酮饮食或补充3HB可增强PD-1单抗及CTLA-4单抗在小鼠中的抗肿瘤作用;
  • 补充蔗糖(抑制3HB产生)或使用GPR109A(3HB受体)拮抗剂处理,可抵消生酮饮食的抗肿瘤作用及对ICB疗效的增强作用;
  • 机制上,3HB抑制巨噬细胞(而非肿瘤细胞)的PD-L1表达,并促进CXCR3+ T细胞的扩增;
  • 生酮饮食诱导肠道菌群中的Eisenbergiella massiliensis的丰度增加,后者与血清3HB浓度呈正相关。
主编推荐语
szx
JCI insight上发表的一项最新研究,发现生酮饮食诱导产生的酮体——3HB可通过抑制巨噬细胞的PD-L1表达,并促进CXCR3+ T细胞扩增,从而在小鼠体内发挥抗肿瘤作用,并增强免疫检查点抑制剂(ICB)——PD-1单抗及CTLA-4单抗的治疗效果。
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JCI insight [IF:6.205]

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

2020-12-15, Article

Abstract & Authors:展开

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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

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