2. Academic Validation
  3. A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers

A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers

  • Science. 2023 Jun 9;380(6649):eabo2296. doi: 10.1126/science.abo2296.
Marine Fidelle # 1 2 3,  Conrad Rauber # 1 2 3 4,  Carolina Alves Costa Silva # 1 2 3,  Ai-Ling Tian 1 2 5 6,  Imran Lahmar 1 2 3,  Anne-Laure Mallard de La Varende 1 2 3,  Liwei Zhao 1 5 6,  Cassandra Thelemaque 1 3,  Isabelle Lebhar 1 3,  Meriem Messaoudene 7,  Eugenie Pizzato 1 3,  Roxanne Birebent 1 2 3,  Maxime Descartes Mbogning Fonkou 1 3,  Silvia Zoppi 1 2 8,  Anna Reni 1 2 9,  Cécile Dalban 10,  Marion Leduc 1 5 6,  Gladys Ferrere 1 3 11,  Sylvère Durand 1 5 6,  Pierre Ly 1 3 12,  Aymeric Silvin 1 3,  Kevin Mulder 1 2 3,  Charles-Antoine Dutertre 1 3,  Florent Ginhoux 1 3,  Satoru Yonekura 1 2 3,  Maria Paula Roberti 1 3 13 14,  Maryam Tidjani-Alou 1 3,  Safae Terrisse 1 2 3,  Jianzhou Chen 1 3,  Oliver Kepp 1 5 6,  Angela Schippers 15,  Norbert Wagner 15,  Javier Suárez-Gosálvez 16,  Sebastian Kobold 16 17,  Jean-Eudes Fahrner 1 2 3,  Corentin Richard 7,  Jacques Bosq 18,  Leonardo Lordello 1 3,  Giacomo Vitali 19,  Nathalie Galleron 19,  Benoît Quinquis 19,  Emmanuelle Le Chatelier 19,  Lucas Blanchard 20,  Jean-Philippe Girard 20,  Anne Jarry 21,  Nadine Gervois 21,  Emmanuelle Godefroy 21,  Nathalie Labarrière 21 22,  Ronald Koschny 4,  Romain Daillère 11,  Benjamin Besse 1 2,  Caroline Truntzer 23,  François Ghiringhelli 23,  Nicolas Coatnoan 24 25,  Vanessa Mhanna 24 25,  David Klatzmann 24 25,  Damien Drubay 1 26 27,  Laurence Albiges 1 2,  Andrew Maltez Thomas 28,  Nicola Segata 28 29,  François-Xavier Danlos 1 2 3 12 30,  Aurélien Marabelle 1 2 3 12 30,  Bertrand Routy 7 31,  Lisa Derosa # 1 2 3 12,  Guido Kroemer # 5 6 32,  Laurence Zitvogel # 1 2 3 12
Affiliations

Affiliations

  • 1 Gustave Roussy Cancer Campus, Villejuif Cedex, France.
  • 2 Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France.
  • 3 Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France.
  • 4 Department of Gastroenterology and Infectious Diseases, University Hospital Heidelberg, Heidelberg, Germany.
  • 5 Centre de Recherche des Cordeliers, INSERM U1138, Équipe Labellisée - Ligue Nationale contre le Cancer, Université Paris Cité, Sorbonne Université, Paris, France.
  • 6 Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
  • 7 Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, Canada.
  • 8 Department of Medicine and Surgery, University of Parma, Parma, Italy.
  • 9 Section of Oncology, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, Verona, Italy.
  • 10 Clinical Research Department, Centre Léon Bérard, Lyon, France.
  • 11 EverImmune, Gustave Roussy Cancer Campus, Villejuif Cedex, France.
  • 12 Center of Clinical Investigations in Biotherapies of Cancer (BIOTHERIS), Villejuif, France.
  • 13 Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 14 Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD), Heidelberg, Germany.
  • 15 Department of Pediatrics, University Hospital RWTH Aachen, Aachen, Germany.
  • 16 Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, LMU Munich, Germany.
  • 17 German Cancer Consortium (DKTK), partner site Munich, Munich, Germany.
  • 18 JBO Consultant, Paris, France.
  • 19 MetaGenoPolis, INRAe, Université Paris-Saclay, Jouy en Josas, France.
  • 20 Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.
  • 21 Nantes Université, Université d'Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302/EMR6001, Nantes, France.
  • 22 LabEx IGO, Université de Nantes, Nantes, France.
  • 23 Université de Bourgogne Franche-Comté, Plateforme de Transfert de Biologie du Cancer, Centre Georges-François Leclerc, Equipe Labellisée Ligue Nationale Contre le Cancer, Centre de Recherche INSERM LNC-UMR1231, Institut Médical de Génétique et d'Immunologie, Dijon, France.
  • 24 AP-HP, Hôpital Pitié-Salpêtrière, Clinical Investigation Center for Biotherapies (CIC-BTi) and Immunology-Inflammation-Infectiology and Dermatology Department (3iD), Paris, France.
  • 25 Sorbonne Université, INSERM, UMRS959 Immunology-Immunopathology-Immunotherapy Laboratory, Paris, France.
  • 26 Office of Biostatistics and Epidemiology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.
  • 27 Inserm, Université Paris-Saclay, CESP U1018, Oncostat, labeled Ligue Contre le Cancer, Villejuif, France.
  • 28 Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy.
  • 29 Istituto Europeo di Oncologia (IEO), National Cancer Institute (IRCCS), Milan, Italy.
  • 30 Drug Development Department, Gustave Roussy Cancer Campus, Villejuif Cedex, France.
  • 31 Hematology-Oncology Division, Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Quebec, Canada.
  • 32 Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.
  • # Contributed equally.
PMID: 37289890 DOI: 10.1126/science.abo2296
Abstract

Antibiotics (ABX) compromise the efficacy of programmed cell death protein 1 (PD-1) blockade in Cancer patients, but the mechanisms underlying their immunosuppressive effects remain unknown. By inducing the down-regulation of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the ileum, post-ABX gut recolonization by Enterocloster species drove the emigration of enterotropic α4β7+CD4+ regulatory T 17 cells into the tumor. These deleterious ABX effects were mimicked by oral gavage of Enterocloster species, by genetic deficiency, or by antibody-mediated neutralization of MAdCAM-1 and its receptor, α4β7 Integrin. By contrast, fecal microbiota transplantation or interleukin-17A neutralization prevented ABX-induced immunosuppression. In independent lung, kidney, and bladder Cancer patient cohorts, low serum levels of soluble MAdCAM-1 had a negative prognostic impact. Thus, the MAdCAM-1-α4β7 axis constitutes an actionable gut Immune Checkpoint in Cancer immunosurveillance.

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