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
  • 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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