A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers
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Fidelle, Marine | Rauber, Conrad | Alves Costa Silva, Carolina | Tian, Ai-Ling | Lahmar, Imran | de la Varende, Anne-Laure Mallard | Zhao, Liwei | Thélémaque, Cassandra | Lebhar, Isabelle | Messaoudene, Meriem | Pizzato, Eugenie | Birebent, Roxanne | Mbogning Fonkou, Maxime Descartes | Zoppi, Silvia | Reni, Anna | Dalban, Cécile | Leduc, Marion | Ferrere, Gladys | Durand, Sylvère | Ly, Pierre | Silvin, Aymeric | Mulder, Kevin | Dutertre, Charles-Antoine | Ginhoux, Florent | Yonekura, Satoru | Roberti, Maria Paula | Tidjani-Alou, Maryam | Terrisse, Safae | Chen, Jianzhou | Kepp, Oliver | Schippers, Angela | Wagner, Norbert | Suárez-Gosálvez, Javier | Kobold, Sebastian | Fahrner, Jean-Eudes | Richard, Corentin | Bosq, Jacques | Lordello, Leonardo | Vitali, Giacomo | Galleron, Nathalie | Quinquis, Benoît | Le Chatelier, Emmanuelle | Blanchard, Lucas | Girard, Jean-Philippe | Jarry, Anne | Gervois, Nadine | Godefroy, Emmanuelle | Labarrière, Nathalie | Koschny, Ronald | Daillère, Romain | Besse, Benjamin | Truntzer, Caroline | Ghiringhelli, François | Coatnoan, Nicolas | Mhanna, Vanessa | Klatzmann, David | Drubay, Damien | Albiges, Laurence | Thomas, Andrew Maltez | Segata, Nicola | Danlos, François-Xavier | Marabelle, Aurélien | Routy, Bertrand | Derosa, Lisa | Kroemer, Guido | Zitvogel, Laurence
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International audience.
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.
