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

Fidelle, Marine; Rauber, Conrad; Alves Costa Silva, Carolina; Tian, Ai-Ling; Lahmar, Imran; de La Varende, Anne-Laure Mallard; Zhao, Liwei; Thelemaque, 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; Pierre, Ly; 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

doi:10.1126/science.abo2296

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.

A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers / Fidelle, Marine; Rauber, Conrad; Alves Costa Silva, Carolina; Tian, Ai-Ling; Lahmar, Imran; de La Varende, Anne-Laure Mallard; Zhao, Liwei; Thelemaque, 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. - In: SCIENCE. - ISSN 1095-9203. - 380:6649(2023), pp. eabo229601-eabo229618. [10.1126/science.abo2296]