由微生物群调节的免疫抑制性肠道T细胞进入肿瘤

法国巴黎萨克雷大学Laurence Zitvogel等研究人员合作发现，一种由微生物群调节的检查点引导免疫抑制性肠道T细胞进入肿瘤。2023年6月9日，国际知名学术期刊《科学》发表了这一成果。

通过诱导回肠中粘膜地址素细胞粘附分子1（MAdCAM-1）的下调，抗生素（ABX）后肠道中的Enterocloster物种重新定居，促使肠道中的α4β7⁺CD4⁺调节性T17细胞迁移到肿瘤中。这些有害的ABX效应通过口服Enterocloster物种、基因缺陷、或抗体介导的MAdCAM-1及其受体α4β7整合素的中和得以模拟。

相比之下，粪便微生物群移植或白细胞介素-17A中和可防止ABX引起的免疫抑制。在独立的肺癌、肾癌和膀胱癌患者群中，可溶性MAdCAM-1的低血清水平对预后有负面影响。因此，MAdCAM-1-α4β7轴构成了癌症免疫监视中可操控的肠道免疫检查点。

据介绍，ABX损害了癌症患者程序性细胞死亡蛋白1（PD-1）阻断的疗效，但其免疫抑制作用的机制仍然未知。

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.