由微生物群調節的免疫抑制性腸道T細胞進入腫瘤

法國巴黎薩克雷大學Laurence Zitvogel等研究人員合作發現，一種由微生物群調節的檢查點引導免疫抑制性腸道T細胞進入腫瘤。2023年6月9日，國際知名學術期刊《科學》發表了這一成果。

通過誘導回腸中粘膜地址素細胞粘附分子1（MAdCAM-1）的下調，抗生素（ABX）后腸道中的Enterocloster物種重新定居，促使腸道中的α4β7⁺CD4⁺調節性T17細胞遷移到腫瘤中。這些有害的ABX效應通過口服Enterocloster物種、基因缺陷、或抗體介導的MAdCAM-1及其受體α4β7整合素的中和得以模擬。

相比之下，糞便微生物群移植或白細胞介素-17A中和可防止ABX引起的免疫抑制。在獨立的肺癌、腎癌和膀胱癌患者群中，可溶性MAdCAM-1的低血清水平對預后有負面影響。因此，MAdCAM-1-α4β7軸構成了癌癥免疫監視中可操控的腸道免疫檢查點。

據介紹，ABX損害了癌癥患者程序性細胞死亡蛋白1（PD-1）阻斷的療效，但其免疫抑制作用的機制仍然未知。

附：英文原文

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

Author: Marine Fidelle, Conrad Rauber, Carolina Alves Costa Silva, Ai-Ling Tian, Imran Lahmar, Anne-Laure Mallard de La Varende, Liwei Zhao, Cassandra Thelemaque, Isabelle Lebhar, Meriem Messaoudene, Eugenie 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, Maria 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, Benot 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, Franois Ghiringhelli, Nicolas Coatnoan, Vanessa Mhanna, David Klatzmann, Damien Drubay, Laurence Albiges, Andrew Maltez Thomas, Nicola Segata, Franois-Xavier Danlos, Aurélien Marabelle, Bertrand Routy, Lisa Derosa, Guido Kroemer, Laurence Zitvogel

Issue&Volume: 2023-06-09

Abstract: 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.