Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance

Federico Pietrocola; Jonathan Pol; Erika Vacchelli; Shuan Rao; David P. Enot; Elisa E. Baracco; Sarah Levesque; Francesca Castoldi; Nicolas Jacquelot; Takahiro Yamazaki; Laura Senovilla; Guillermo Marino; Fernando Aranda; Sylvère Durand; Valentina Sica; Alexis Chery; Sylvie Lachkar; Verena Sigl; Norma Bloy; Aitziber Buque; Simonetta Falzoni; Bernhard Ryffel; Lionel Apetoh; Francesco Di Virgilio; Frank Madeo; Maria Chiara Maiuri; Laurence Zitvogel; Beth Levine; Josef M. Penninger; Guido Kroemer

doi:10.1016/j.ccell.2016.05.016

Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance

Federico Pietrocola, Jonathan Pol, Erika Vacchelli, Shuan Rao, David P. Enot, Elisa E. Baracco, Sarah Levesque, Francesca Castoldi, Nicolas Jacquelot, Takahiro Yamazaki, Laura Senovilla, Guillermo Marino, Fernando Aranda, Sylvère Durand, Valentina Sica, Alexis Chery, Sylvie Lachkar, Verena Sigl, Norma Bloy, Aitziber BuqueSimonetta Falzoni, Bernhard Ryffel, Lionel Apetoh, Francesco Di Virgilio, Frank Madeo, Maria Chiara Maiuri, Laurence Zitvogel, Beth Levine, Josef M. Penninger, Guido Kroemer

Research output: Contribution to journal › Article › peer-review

343 Scopus citations

Abstract

Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.

Original language	English (US)
Pages (from-to)	147-160
Number of pages	14
Journal	Cancer Cell
Volume	30
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2016.05.016
State	Published - Jul 11 2016

Keywords

cancer
chemotherapy
immunosurveillance
regulatory T cell

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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10.1016/j.ccell.2016.05.016

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Pietrocola, F., Pol, J., Vacchelli, E., Rao, S., Enot, D. P., Baracco, E. E., Levesque, S., Castoldi, F., Jacquelot, N., Yamazaki, T., Senovilla, L., Marino, G., Aranda, F., Durand, S., Sica, V., Chery, A., Lachkar, S., Sigl, V., Bloy, N., ... Kroemer, G. (2016). Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance. Cancer Cell, 30(1), 147-160. https://doi.org/10.1016/j.ccell.2016.05.016

Pietrocola, F, Pol, J, Vacchelli, E, Rao, S, Enot, DP, Baracco, EE, Levesque, S, Castoldi, F, Jacquelot, N, Yamazaki, T, Senovilla, L, Marino, G, Aranda, F, Durand, S, Sica, V, Chery, A, Lachkar, S, Sigl, V, Bloy, N, Buque, A, Falzoni, S, Ryffel, B, Apetoh, L, Di Virgilio, F, Madeo, F, Maiuri, MC, Zitvogel, L, Levine, B, Penninger, JM & Kroemer, G 2016, 'Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance', Cancer Cell, vol. 30, no. 1, pp. 147-160. https://doi.org/10.1016/j.ccell.2016.05.016

@article{ef5211b73d1b404e9eaa3b6aa4201c60,

title = "Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance",

abstract = "Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.",

keywords = "cancer, chemotherapy, immunosurveillance, regulatory T cell",

author = "Federico Pietrocola and Jonathan Pol and Erika Vacchelli and Shuan Rao and Enot, {David P.} and Baracco, {Elisa E.} and Sarah Levesque and Francesca Castoldi and Nicolas Jacquelot and Takahiro Yamazaki and Laura Senovilla and Guillermo Marino and Fernando Aranda and Sylv{\`e}re Durand and Valentina Sica and Alexis Chery and Sylvie Lachkar and Verena Sigl and Norma Bloy and Aitziber Buque and Simonetta Falzoni and Bernhard Ryffel and Lionel Apetoh and {Di Virgilio}, Francesco and Frank Madeo and Maiuri, {Maria Chiara} and Laurence Zitvogel and Beth Levine and Penninger, {Josef M.} and Guido Kroemer",

note = "Funding Information: G.K. and L.Z. are supported by the Ligue Nationale contre le Cancer (Equipes labellis{\'e}es), Site de Recherche Int{\'e}gr{\'e}e sur le Cancer (IRIC) Socrates, the ISREC Foundation , Agence Nationale pour la Recherche (ANR AUTOPH, ANR Emergence), the European Commission (ArtForce), a European Research Council Advanced Investigator Grant (to G.K.), the Fondation pour la Recherche M{\'e}dicale (FRM), the Institut National du Cancer (INCa), the Fondation de France , Canc{\'e}rop{\^o}le Ile-de-France , the Fondation Bettencourt-Schueller , the LabEx Immuno-Oncology , and the Paris Alliance of Cancer Research Institutes . J.M.P. is supported by EU network grants Apo-Sys ApoSys and InflaCare , an advanced ERC grant, and an Era of Hope/DoD Innovator Award. F.M. is grateful to the FWF for grants LIPOTOX , I1000, P23490-B12 , and P24381-B20 , and the BMWFW for grant Unconventional research. F.D.V. is supported by grants from the AIRC (no. IG5354 ), Telethon (no. GGP06070 ), ERA-NET Neuron “Nanostroke”, the Ministry of Health of Italy (no. RF-2011-02348435 ), the Italian Ministry of Education, University and Research (no. RBAP11FXBC_001 ), and funds from the University of Ferrara . B.L. is supported by NIH grants RO1CA109618 and U19 AI109725 , and Cancer Prevention and Research Institute of Texas grant RP120718 . E.E.B. is supported by Canc{\'e}rop{\^o}le Ile-de-France . We thank Prof. Eric Tartour and Dr. Johannes Ludger for TC1-specific HPV16-E7 tetramer. We are grateful to Dr. Lorenzo Galluzzi for the extensive proofreading of manuscript and figures. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = jul,

day = "11",

doi = "10.1016/j.ccell.2016.05.016",

language = "English (US)",

volume = "30",

pages = "147--160",

journal = "Cancer Cell",

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publisher = "Cell Press",

number = "1",

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TY - JOUR

T1 - Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance

AU - Pietrocola, Federico

AU - Pol, Jonathan

AU - Vacchelli, Erika

AU - Rao, Shuan

AU - Enot, David P.

AU - Baracco, Elisa E.

AU - Levesque, Sarah

AU - Castoldi, Francesca

AU - Jacquelot, Nicolas

AU - Yamazaki, Takahiro

AU - Senovilla, Laura

AU - Marino, Guillermo

AU - Aranda, Fernando

AU - Durand, Sylvère

AU - Sica, Valentina

AU - Chery, Alexis

AU - Lachkar, Sylvie

AU - Sigl, Verena

AU - Bloy, Norma

AU - Buque, Aitziber

AU - Falzoni, Simonetta

AU - Ryffel, Bernhard

AU - Apetoh, Lionel

AU - Di Virgilio, Francesco

AU - Madeo, Frank

AU - Maiuri, Maria Chiara

AU - Zitvogel, Laurence

AU - Levine, Beth

AU - Penninger, Josef M.

AU - Kroemer, Guido

N1 - Funding Information: G.K. and L.Z. are supported by the Ligue Nationale contre le Cancer (Equipes labellisées), Site de Recherche Intégrée sur le Cancer (IRIC) Socrates, the ISREC Foundation , Agence Nationale pour la Recherche (ANR AUTOPH, ANR Emergence), the European Commission (ArtForce), a European Research Council Advanced Investigator Grant (to G.K.), the Fondation pour la Recherche Médicale (FRM), the Institut National du Cancer (INCa), the Fondation de France , Cancéropôle Ile-de-France , the Fondation Bettencourt-Schueller , the LabEx Immuno-Oncology , and the Paris Alliance of Cancer Research Institutes . J.M.P. is supported by EU network grants Apo-Sys ApoSys and InflaCare , an advanced ERC grant, and an Era of Hope/DoD Innovator Award. F.M. is grateful to the FWF for grants LIPOTOX , I1000, P23490-B12 , and P24381-B20 , and the BMWFW for grant Unconventional research. F.D.V. is supported by grants from the AIRC (no. IG5354 ), Telethon (no. GGP06070 ), ERA-NET Neuron “Nanostroke”, the Ministry of Health of Italy (no. RF-2011-02348435 ), the Italian Ministry of Education, University and Research (no. RBAP11FXBC_001 ), and funds from the University of Ferrara . B.L. is supported by NIH grants RO1CA109618 and U19 AI109725 , and Cancer Prevention and Research Institute of Texas grant RP120718 . E.E.B. is supported by Cancéropôle Ile-de-France . We thank Prof. Eric Tartour and Dr. Johannes Ludger for TC1-specific HPV16-E7 tetramer. We are grateful to Dr. Lorenzo Galluzzi for the extensive proofreading of manuscript and figures. Publisher Copyright: © 2016 Elsevier Inc.

PY - 2016/7/11

Y1 - 2016/7/11

N2 - Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.

AB - Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.

KW - cancer

KW - chemotherapy

KW - immunosurveillance

KW - regulatory T cell

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U2 - 10.1016/j.ccell.2016.05.016

DO - 10.1016/j.ccell.2016.05.016

M3 - Article

C2 - 27411589

AN - SCOPUS:84979780741

SN - 1535-6108

VL - 30

SP - 147

EP - 160

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance

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Keywords

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