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

• 成果类型: Article
• 署名作者: Fidelle, Marine; Rauber, Conrad; Silva, Carolina Alves Costa; Tian, Ai-Ling; Lahmar, Imran; de La Varende, Anne-Laure Mallard; Zhao, Liwei; Thelemaque, Cassandra; Lebhar, Isabelle; Messaoudene, Meriem; Pizzato, Eugenie; Birebent, Roxanne; Fonkou, Maxime Descartes Mbogning; Zoppi, Silvia; Reni, Anna; Dalban, Cecile; Leduc, Marion; Ferrere, Gladys; Durand, Sylvere; 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; Suarez-Gosalvez, Javier; Kobold, Sebastian; Fahrner, Jean-Eudes; Richard, Corentin; Bosq, Jacques; Lordello, Leonardo; Vitali, Giacomo; Galleron, Nathalie; Quinquis, Benoit; Le Chatelier, Emmanuelle; Blanchard, Lucas; Girard, Jean-Philippe; Jarry, Anne; Gervois, Nadine; Godefroy, Emmanuelle; Labarriere, Nathalie; Koschny, Ronald; Daillere, Romain; Besse, Benjamin; Truntzer, Caroline; Ghiringhelli, Francois; Coatnoan, Nicolas; Mhanna, Vanessa; Klatzmann, David; Drubay, Damien; Albiges, Laurence; Thomas, Andrew Maltez; Segata, Nicola; Danlos, Francois-Xavier; Marabelle, Aurelien; Routy, Bertrand; Derosa, Lisa; Kroemer, Guido; Zitvogel, Laurence
• 署名单位: UNICANCER; Gustave Roussy; Universite Paris Saclay; Institut National de la Sante et de la Recherche Medicale (Inserm); Ruprecht Karls University Heidelberg; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Sorbonne Universite; UNICANCER; Gustave Roussy; Universite de Montreal; University of Parma; University of Verona; University of Verona; Azienda Ospedaliera Universitaria Integrata Verona; UNICANCER; Centre Leon Berard; UNICANCER; Gustave Roussy; Helmholtz Association; German Cancer Research Center (DKFZ); Helmholtz Association; German Cancer Research Center (DKFZ); Ruprecht Karls University Heidelberg; National Center for Tumor Diseases; RWTH Aachen University; RWTH Aachen University Hospital; University of Munich; University of Munich; Helmholtz Association; German Cancer Research Center (DKFZ); Universite Paris Saclay; INRAE; Universite de Toulouse; Universite Toulouse III - Paul Sabatier; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite d'Angers; Centre National de la Recherche Scientifique (CNRS); Nantes Universite; Nantes Universite; Institut Agro; AgroSup Dijon; UNICANCER; Universite Bourgogne Europe; Centre Georges-Francois Leclerc; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Pitie-Salpetriere - APHP; Sorbonne Universite; Sorbonne Universite; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Pitie-Salpetriere - APHP; Institut National de la Sante et de la Recherche Medicale (Inserm); Sorbonne Universite; Universite Paris Saclay; UNICANCER; Gustave Roussy; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Saclay; University of Trento; IRCCS European Institute of Oncology (IEO); UNICANCER; Gustave Roussy; Universite de Montreal; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Europeen Georges-Pompidou - APHP
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9043
• DOI: 10.1126/science.abo2296
• 发表日期: 2023-06-09
• 关键词: gene-expression; beta-7+t cells; resistance; therapy; immunotherapy; population; signature; responses; disease; cd4(+)

摘要

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 a4b7+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, a4b7 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-a4b7 axis constitutes an actionable gut immune checkpoint in cancer immunosurveillance.