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 journalArticlepeer-review

128 Scopus citations


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.

Original languageEnglish
Pages (from-to)919-931
Number of pages13
JournalNature Medicine
Issue number6
StatePublished - 1 Jun 2020
Externally publishedYes

Bibliographical note

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


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).

FundersFunder number
BMS Foundation
Cancer PlanHTE201601
Cancéropôle Ile-de-France
FHU CARE, Dassault and Badinter Philantropia
Fondation Carrefour
National Alliance for Life Sciences & Health
Horizon 2020 Framework Programme825410
Seerave Foundation
European Commission
European Research Council
Deutsche ForschungsgemeinschaftCRC1181-A7
Agence Nationale de la RechercheANR-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 Fund2016-00110366, EX005756
Conseil Général Département des Bouches du Rhône
Chancellerie des Universités de Paris
ITMO University
Labex Immuno-OncologyANR-16-RHUS-0008


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