Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer

Maria Paula Roberti; Satoru Yonekura; Connie P.M. Duong; Marion Picard; Gladys Ferrere; Maryam Tidjani Alou; Conrad Rauber; Valerio Iebba; Christian H.K. Lehmann; Lukas Amon; Diana Dudziak; Lisa Derosa; Bertrand Routy; Caroline Flament; Corentin Richard; Romain Daillère; Aurélie Fluckiger; Isabelle Van Seuningen; Mathias Chamaillard; Audrey Vincent; Stephanie Kourula; Paule Opolon; Pierre Ly; Eugénie Pizzato; Sonia Becharef; Juliette Paillet; Christophe Klein; Florence Marliot; Filippo Pietrantonio; Stéphane Benoist; Jean Yves Scoazec; Peggy Dartigues; Antoine Hollebecque; David Malka; Franck Pagès; Jérôme Galon; Ivo Gomperts Boneca; Patricia Lepage; Bernard Ryffel; Didier Raoult; Alexander Eggermont; Tom Vanden Berghe; François Ghiringhelli; Peter Vandenabeele; Guido Kroemer; Laurence Zitvogel

doi:10.1038/s41591-020-0882-8

Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer

Maria Paula Roberti, Satoru Yonekura, Connie P.M. Duong, Marion Picard, Gladys Ferrere, Maryam Tidjani Alou, Conrad Rauber, Valerio Iebba, Christian H.K. Lehmann, Lukas Amon, Diana Dudziak, Lisa Derosa, Bertrand Routy, Caroline Flament, Corentin Richard, Romain Daillère, Aurélie Fluckiger, Isabelle Van Seuningen, Mathias Chamaillard, Audrey VincentStephanie Kourula, Paule Opolon, Pierre Ly, Eugénie Pizzato, Sonia Becharef, Juliette Paillet, Christophe Klein, Florence Marliot, Filippo Pietrantonio, Stéphane Benoist, Jean Yves Scoazec, Peggy Dartigues, Antoine Hollebecque, David Malka, Franck Pagès, Jérôme Galon, Ivo Gomperts Boneca, Patricia Lepage, Bernard Ryffel, Didier Raoult, Alexander Eggermont, Tom Vanden Berghe, François Ghiringhelli, Peter Vandenabeele, Guido Kroemer, Laurence Zitvogel

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

153 Scopus citations

Abstract

The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (T_FH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of T_FH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of T_FH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1⁺ T_FH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.

Original language	English
Pages (from-to)	919-931
Number of pages	13
Journal	Nature Medicine
Volume	26
Issue number	6
DOIs	https://doi.org/10.1038/s41591-020-0882-8
State	Published - 1 Jun 2020
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding

We thank the animal facility team at Gustave Roussy. We thank technicians and pathologists from Centre GF Leclerc: L. Guyard, L. Arnould and S. Ladoire. We thank S. Brutin, A. Paci, M. Vétizou, T. Yamazaki, J.-E. Fahrner and A. G. Goubet for technical assistance. We thank D. Goere, R. Bonnet, P. Sauvanet, D. Pezet, J. Gagnière, F. Pagani and A. Martinetti for helping with human samples collection. We thank M. Merad, for scientific advice. We thank R. Förster (Institut für Immunologie) and J. A. Harker (Imperial College) for providing knockout models. L.Z. and G.K. were supported by the Ligue Contre le Cancer (Equipe Labelisée); Agence Nationale de la Recherche (ANR) Francogermanique ANR-19-CE15-0029, ANR Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la Recherche sur le Cancer; BMS Foundation, Cancéropôle Ile-de-France; Chancelerie des Universités de Paris (Legs Poix), Fondation pour la Recherche Médicale; a donation by Elior; the European Commission (ArtForce); the European Research Council; Fondation Carrefour; Institut National du Cancer; Inserm; Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumière (ANR-16-RHUS-0008); H2020 ONCOBIOME, the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination; the SIRIC Cancer Research and Personalized Medicine (CARPEM); FHU CARE, Dassault and Badinter Philantropia and the Paris Alliance of Cancer Research Institutes. D.D. was supported by the German Research Foundation (CRC1181-A7). B. Ryffel was supported by Centre National de la Recherche Scientifique, the University of Orleans, the Conseil Général du Loiret and European Regional Development Fund (FEDER No. 2016-00110366 and EX005756). M.C. was supported by ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Santé, National Alliance for Life Sciences & Health) within the framework of the Cancer Plan (HTE201601).

Funders	Funder number
BMS Foundation
Cancer Plan	HTE201601
Cancéropôle Ile-de-France
FHU CARE, Dassault and Badinter Philantropia
Fondation Carrefour
H2020 ONCOBIOME
National Alliance for Life Sciences & Health
Horizon 2020 Framework Programme	825410
Seerave Foundation
European Commission
European Commission
Deutsche Forschungsgemeinschaft	CRC1181-A7
Agence Nationale de la Recherche	ANR-19-CE15-0029
Fondation Leducq
Institut national de la santé et de la recherche médicale
Fondation pour la Recherche Médicale
Ligue Contre le Cancer
Centre National de la Recherche Scientifique
Institut universitaire de France
Agence Nationale pour le Développement de la Recherche en Santé
Institut National du Cancer
European Regional Development Fund	2016-00110366, EX005756
Conseil Général Département des Bouches du Rhône
Chancellerie des Universités de Paris
ITMO University
Labex Immuno-Oncology	ANR-16-RHUS-0008

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41591-020-0882-8

Cite this

Roberti, M. P., Yonekura, S., Duong, C. P. M., Picard, M., Ferrere, G., Tidjani Alou, M., Rauber, C., Iebba, V., Lehmann, C. H. K., Amon, L., Dudziak, D., Derosa, L., Routy, B., Flament, C., Richard, C., Daillère, R., Fluckiger, A., Van Seuningen, I., Chamaillard, M., ... Zitvogel, L. (2020). Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer. Nature Medicine, 26(6), 919-931. https://doi.org/10.1038/s41591-020-0882-8

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abstract = "The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of TFH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1+ TFH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.",

author = "Roberti, {Maria Paula} and Satoru Yonekura and Duong, {Connie P.M.} and Marion Picard and Gladys Ferrere and {Tidjani Alou}, Maryam and Conrad Rauber and Valerio Iebba and Lehmann, {Christian H.K.} and Lukas Amon and Diana Dudziak and Lisa Derosa and Bertrand Routy and Caroline Flament and Corentin Richard and Romain Daill{\`e}re and Aur{\'e}lie Fluckiger and {Van Seuningen}, Isabelle and Mathias Chamaillard and Audrey Vincent and Stephanie Kourula and Paule Opolon and Pierre Ly and Eug{\'e}nie Pizzato and Sonia Becharef and Juliette Paillet and Christophe Klein and Florence Marliot and Filippo Pietrantonio and St{\'e}phane Benoist and Scoazec, {Jean Yves} and Peggy Dartigues and Antoine Hollebecque and David Malka and Franck Pag{\`e}s and J{\'e}r{\^o}me Galon and {Gomperts Boneca}, Ivo and Patricia Lepage and Bernard Ryffel and Didier Raoult and Alexander Eggermont and {Vanden Berghe}, Tom and Fran{\c c}ois Ghiringhelli and Peter Vandenabeele and Guido Kroemer and Laurence Zitvogel",

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doi = "10.1038/s41591-020-0882-8",

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Roberti, MP, Yonekura, S, Duong, CPM, Picard, M, Ferrere, G, Tidjani Alou, M, Rauber, C, Iebba, V, Lehmann, CHK, Amon, L, Dudziak, D, Derosa, L, Routy, B, Flament, C, Richard, C, Daillère, R, Fluckiger, A, Van Seuningen, I, Chamaillard, M, Vincent, A, Kourula, S, Opolon, P, Ly, P, Pizzato, E, Becharef, S, Paillet, J, Klein, C, Marliot, F, Pietrantonio, F, Benoist, S, Scoazec, JY, Dartigues, P, Hollebecque, A, Malka, D, Pagès, F, Galon, J, Gomperts Boneca, I, Lepage, P, Ryffel, B, Raoult, D, Eggermont, A, Vanden Berghe, T, Ghiringhelli, F, Vandenabeele, P, Kroemer, G & Zitvogel, L 2020, 'Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer', Nature Medicine, vol. 26, no. 6, pp. 919-931. https://doi.org/10.1038/s41591-020-0882-8

TY - JOUR

T1 - Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer

AU - Roberti, Maria Paula

AU - Yonekura, Satoru

AU - Duong, Connie P.M.

AU - Picard, Marion

AU - Ferrere, Gladys

AU - Tidjani Alou, Maryam

AU - Rauber, Conrad

AU - Iebba, Valerio

AU - Lehmann, Christian H.K.

AU - Amon, Lukas

AU - Dudziak, Diana

AU - Derosa, Lisa

AU - Routy, Bertrand

AU - Flament, Caroline

AU - Richard, Corentin

AU - Daillère, Romain

AU - Fluckiger, Aurélie

AU - Van Seuningen, Isabelle

AU - Chamaillard, Mathias

AU - Vincent, Audrey

AU - Kourula, Stephanie

AU - Opolon, Paule

AU - Ly, Pierre

AU - Pizzato, Eugénie

AU - Becharef, Sonia

AU - Paillet, Juliette

AU - Klein, Christophe

AU - Marliot, Florence

AU - Pietrantonio, Filippo

AU - Benoist, Stéphane

AU - Scoazec, Jean Yves

AU - Dartigues, Peggy

AU - Hollebecque, Antoine

AU - Malka, David

AU - Pagès, Franck

AU - Galon, Jérôme

AU - Gomperts Boneca, Ivo

AU - Lepage, Patricia

AU - Ryffel, Bernard

AU - Raoult, Didier

AU - Eggermont, Alexander

AU - Vanden Berghe, Tom

AU - Ghiringhelli, François

AU - Vandenabeele, Peter

AU - Kroemer, Guido

AU - Zitvogel, Laurence

PY - 2020/6/1

Y1 - 2020/6/1

N2 - The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of TFH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1+ TFH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.

AB - The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of TFH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1+ TFH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.

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U2 - 10.1038/s41591-020-0882-8

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SN - 1078-8956

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JF - Nature Medicine

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ER -

Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer

Abstract

Bibliographical note

Funding

UN SDGs

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