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

Nat Med. 2020 Jun;26(6):919-931. doi: 10.1038/s41591-020-0882-8. Epub 2020 May 25.

Authors

Maria Paula Roberti^{1

2

3}, Satoru Yonekura^{1

2

4}, Connie P M Duong^{1

2}, Marion Picard^{1

2

5}, Gladys Ferrere^{1

2}, Maryam Tidjani Alou^{1

2}, Conrad Rauber^{1

2

4}, Valerio Iebba^{1

2}, Christian H K Lehmann⁶, Lukas Amon⁶, Diana Dudziak⁶, Lisa Derosa^{1

2

3}, Bertrand Routy^{1

2

4}, Caroline Flament^{1

2

3}, Corentin Richard^{7

8}, Romain Daillère^{1

2}, Aurélie Fluckiger^{1

2}, Isabelle Van Seuningen⁹, Mathias Chamaillard¹⁰, Audrey Vincent⁹, Stephanie Kourula^{11

12}, Paule Opolon¹, Pierre Ly^{1

2}, Eugénie Pizzato^{1

2}, Sonia Becharef^{1

2}, Juliette Paillet^{4

13

14}, Christophe Klein¹³, Florence Marliot^{15

16}, Filippo Pietrantonio^{17

18}, Stéphane Benoist¹⁹, Jean-Yves Scoazec²⁰, Peggy Dartigues²⁰, Antoine Hollebecque²¹, David Malka²¹, Franck Pagès^{15

16}, Jérôme Galon^{15

16}, Ivo Gomperts Boneca^{5

22}, Patricia Lepage²³, Bernard Ryffel²⁴, Didier Raoult²⁵, Alexander Eggermont^{1

2

21}, Tom Vanden Berghe^{11

12}, François Ghiringhelli^{7

8}, Peter Vandenabeele^{11

12

26}, Guido Kroemer^{13

14

27

28

29}, Laurence Zitvogel^{30

31

32

33

34}

Affiliations

¹ Gustave Roussy Cancer Campus (GRCC), Villejuif, France.
² Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France.
³ Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France.
⁴ Université Paris-Saclay, Le Kremlin-Bicêtre cedex, France.
⁵ Unit Biology and Genetics of the Bacterial Cell Wall, Institut Pasteur Paris, Paris, France.
⁶ Department of Dermatology, Laboratory of Dendritic Cell Biology, Medical Immunology Campus Erlangen, University Hospital of Erlangen, Friedrich-Alexander-University (FAU) of Erlangen-Nürnberg, Erlangen, Germany.
⁷ Department of Medical Oncology, Center GF Leclerc, Dijon, France.
⁸ Plateform Transfer in Biological Oncology, Dijon, France.
⁹ Inserm UMR-S 1172, Jean-Pierre Aubert Research Center, CHU Lille, University of Lille, Lille, France.
¹⁰ Laboratory of Cell Physiology, INSERM U1003, University of Lille, Lille, France.
¹¹ Molecular Signaling and Cell Death Unit, VIB Inflammation Research Center, Ghent, Belgium.
¹² Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
¹³ Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France.
¹⁴ Cell Biology and Metabolomics Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
¹⁵ Laboratory of Integrative Cancer Immunology, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France.
¹⁶ Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France.
¹⁷ Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
¹⁸ Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy.
¹⁹ Service de Chirurgie Digestive et Oncologique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
²⁰ Departement de Biologie et Pathologie Médicales, Gustave Roussy Cancer Campus, Villejuif, France.
²¹ Departement de Médicine Oncologique, Gustave Roussy Cancer Campus, Villejuif, France.
²² INSERM, Equipe Avenir, Paris, France.
²³ Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.
²⁴ Molecular Immunology and Embryology, UMR 7355, CNRS, University of Orleans, Orléans, France.
²⁵ Unité des Rickettsies, Faculté de Médecine, Université de la Méditerranée, Marseille, France.
²⁶ Methusalem Program, Ghent University, Ghent, Belgium.
²⁷ Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de, Paris, France.
²⁸ Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.
²⁹ Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
³⁰ Gustave Roussy Cancer Campus (GRCC), Villejuif, France. laurence.zitvogel@gustaveroussy.fr.
³¹ Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France. laurence.zitvogel@gustaveroussy.fr.
³² Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France. laurence.zitvogel@gustaveroussy.fr.
³³ Université Paris-Saclay, Le Kremlin-Bicêtre cedex, France. laurence.zitvogel@gustaveroussy.fr.
³⁴ Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China. laurence.zitvogel@gustaveroussy.fr.

PMID: 32451498
DOI: 10.1038/s41591-020-0882-8

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / drug therapy*
Adenocarcinoma / immunology
Adenocarcinoma / microbiology
Adenocarcinoma / pathology
Adult
Aged
Aged, 80 and over
Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects*
Apoptosis / immunology
Bacteroides fragilis
Cell Line, Tumor
Colonic Neoplasms / drug therapy*
Colonic Neoplasms / immunology
Colonic Neoplasms / microbiology
Colonic Neoplasms / pathology
Epithelial Cells / drug effects
Epithelial Cells / immunology
Epithelial Cells / pathology
Female
Firmicutes
Gastrointestinal Microbiome / immunology*
Gastrointestinal Microbiome / physiology
Humans
Ileum / drug effects*
Ileum / immunology
Ileum / microbiology
Ileum / pathology
Immunogenic Cell Death / drug effects
Immunogenic Cell Death / immunology
Immunologic Surveillance / drug effects
Immunologic Surveillance / immunology
Interleukin-12 / immunology
Intestinal Mucosa
Lymphocytes, Tumor-Infiltrating / drug effects*
Lymphocytes, Tumor-Infiltrating / immunology
Male
Mice
Middle Aged
Oxaliplatin / pharmacology*
Oxaliplatin / therapeutic use
Prognosis
Programmed Cell Death 1 Receptor / antagonists & inhibitors
Receptors, Interleukin-1 Type I / immunology
T-Lymphocytes, Helper-Inducer / drug effects
T-Lymphocytes, Helper-Inducer / immunology

Substances

Antineoplastic Agents
Programmed Cell Death 1 Receptor
Receptors, Interleukin-1 Type I
Oxaliplatin
Interleukin-12