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Get Free AccessAntibiotics (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.
Marine Fidelle, Conrad Rauber, Carolina Alves Costa Silva, Ai-Ling Tian, Imran Lahmar, Anne-Laure Mallard de La Varende, Liwei Zhao, Cassandra Thélémaque, Isabelle Lebhar, Meriem Messaoudene, Eugénie Pizzato, Roxanne Birebent, Maxime Descartes Mbogning Fonkou, Silvia Zoppi, Anna Reni, Cécile Dalban, Marion Leduc, Gladys Ferrere, Sylvère Durand, Pierre Ly, Aymeric Silvin, Kevin Mulder, Charles‐Antoine Dutertre, Florent Ginhoux, Satoru Yonekura, María Paula Roberti, Maryam Tidjani Alou, Safae Terrisse, Jianzhou Chen, Oliver Kepp, Angela Schippers, Norbert Wagner, Javier Suárez-Gosálvez, Sebastian Kobold, Jean‐Eudes Fahrner, Corentin Richard, Jacques Bosq, Leonardo Lordello, Giacomo Vitali, Nathalie Galleron, Benoît Quinquis, Emmanuelle Le Chatelier, Lucas Blanchard, Jean‐Philippe Girard, Anne Jarry, Nadine Gervois, Emmanuelle Godefroy, Nathalie Labarrière, Ronald Koschny, Romain Daillère, Benjamin Besse, Caroline Truntzer, François Ghiringhelli, Nicolas Coatnoan, Vanessa Mhanna, David Klatzmann, Damien Drubay, Laurence Albigès, Andrew Maltez Thomas, Nicola Segata, François‐Xavier Danlos, Aurélien Marabelle, Bertrand Routy, Lisa Derosa, Guido Guido Kroemer, Laurence Zitvogel (2023). A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers. , 380(6649), DOI: https://doi.org/10.1126/science.abo2296.
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Type
Article
Year
2023
Authors
66
Datasets
0
Total Files
0
Language
en
DOI
https://doi.org/10.1126/science.abo2296
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