Gustave Roussy Cancer Campus, Villejuif Cedex, France.
Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France.
Science. 2023 Jun 9;380(6649):eabo2296. 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 species drove the emigration of enterotropic α4β7CD4 regulatory T 17 cells into the tumor. These deleterious ABX effects were mimicked by oral gavage of 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.
抗生素（ABX）会降低癌症患者程序性细胞死亡蛋白 1（PD-1）阻断的疗效，但它们的免疫抑制作用的机制尚不清楚。ABX 后， 种通过诱导回肠中粘膜地址素细胞黏附分子 1（MAdCAM-1）的下调，驱动肠嗜性 α4β7CD4 调节性 T17 细胞进入肿瘤。通过口服 种、遗传缺陷或中和 MAdCAM-1 及其受体 α4β7 整合素的抗体，模拟了这些有害的 ABX 作用。相比之下，粪便微生物群移植或白细胞介素-17A 中和可预防 ABX 诱导的免疫抑制。在独立的肺癌、肾癌和膀胱癌患者队列中，可溶性 MAdCAM-1 血清水平低与预后不良相关。因此，MAdCAM-1-α4β7 轴构成了癌症免疫监视中可操作的肠道免疫检查点。
