A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers.
Marine FidelleConrad RauberCarolina Alves Costa SilvaAi-Ling TianImran LahmarAnne-Laure Mallard de La VarendeLiwei ZhaoCassandra ThelemaqueIsabelle LebharMeriem MessaoudeneEugenie PizzatoRoxanne BirebentMaxime Descartes Mbogning FonkouSilvia ZoppiAnna ReniCécile DalbanMarion LeducGladys FerrereSylvère DurandPierre LyAymeric SilvinKevin MulderCharles-Antoine DutertreFlorent GinhouxSatoru YonekuraMaria Paula RobertiMaryam Tidjani AlouSafae TerrisseJianzhou ChenOliver KeppAngela SchippersNorbert WagnerJavier Suarez-GosalvezSebastian KoboldJean-Eudes FahrnerCorentin RichardJacques BosqLeonardo LordelloGiacomo VitaliNathalie GalleronBenoit QuinquisEmmanuelle Le ChatelierLucas BlanchardJean-Philippe GirardAnne JarryNadine Gervois-SegainEmmanuelle GodefroyNathalie LabarrièreRonald KoschnyRomain DaillèreBenjamin BesseCaroline TruntzerFrançois GhiringhelliNicolas CoatnoanVanessa MhannaDavid KlatzmannDamien DrubayLaurence AlbigesAndrew Maltez ThomasNicola SegataFrançois-Xavier DanlosAurélien MarabelleBertrand RoutyLisa DerosaGuido KroemerLaurence ZitvogelPublished in: Science (New York, N.Y.) (2023)
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.