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.

Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade / Ferrere, Gladys; Tidjani Alou, Maryam; Liu, Peng; Goubet, Anne-Gaëlle; Fidelle, Marine; Kepp, Oliver; Durand, Sylvère; Iebba, Valerio; Fluckiger, Aurélie; Daillère, Romain; Thelemaque, Cassandra; Grajeda-Iglesias, Claudia; Alves Costa Silva, Carolina; Aprahamian, Fanny; Lefevre, Déborah; Zhao, Liwei; Ryffel, Bernhard; Colomba, Emeline; Arnedos, Monica; Drubay, Damien; Rauber, Conrad; Raoult, Didier; Asnicar, Francesco; Spector, Tim; Segata, Nicola; Derosa, Lisa; Kroemer, Guido; Zitvogel, Laurence. - In: JCI INSIGHT. - ISSN 2379-3708. - 6:2(2021), pp. e14520701-e14520718. [10.1172/jci.insight.145207]

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

Asnicar, Francesco;Segata, Nicola;
2021-01-01

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.
2021
2
Ferrere, Gladys; Tidjani Alou, Maryam; Liu, Peng; Goubet, Anne-Gaëlle; Fidelle, Marine; Kepp, Oliver; Durand, Sylvère; Iebba, Valerio; Fluckiger, Aurélie; Daillère, Romain; Thelemaque, Cassandra; Grajeda-Iglesias, Claudia; Alves Costa Silva, Carolina; Aprahamian, Fanny; Lefevre, Déborah; Zhao, Liwei; Ryffel, Bernhard; Colomba, Emeline; Arnedos, Monica; Drubay, Damien; Rauber, Conrad; Raoult, Didier; Asnicar, Francesco; Spector, Tim; Segata, Nicola; Derosa, Lisa; Kroemer, Guido; Zitvogel, Laurence
Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade / Ferrere, Gladys; Tidjani Alou, Maryam; Liu, Peng; Goubet, Anne-Gaëlle; Fidelle, Marine; Kepp, Oliver; Durand, Sylvère; Iebba, Valerio; Fluckiger, Aurélie; Daillère, Romain; Thelemaque, Cassandra; Grajeda-Iglesias, Claudia; Alves Costa Silva, Carolina; Aprahamian, Fanny; Lefevre, Déborah; Zhao, Liwei; Ryffel, Bernhard; Colomba, Emeline; Arnedos, Monica; Drubay, Damien; Rauber, Conrad; Raoult, Didier; Asnicar, Francesco; Spector, Tim; Segata, Nicola; Derosa, Lisa; Kroemer, Guido; Zitvogel, Laurence. - In: JCI INSIGHT. - ISSN 2379-3708. - 6:2(2021), pp. e14520701-e14520718. [10.1172/jci.insight.145207]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/355070
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