Gustave Roussy Cancer Campus (GRCC), Villejuif, France.
Institut National de la Santé et de la Recherche Medicale (INSERM) U1015 and Equipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France.
Science. 2018 Jan 5;359(6371):91-97. doi: 10.1126/science.aan3706. Epub 2017 Nov 2.
Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Oral supplementation with after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9CXCR3CD4 T lymphocytes into mouse tumor beds.
免疫检查点抑制剂（ICIs）针对 PD-1/PD-L1 轴在相当一部分癌症患者中诱导持续的临床反应。我们发现，对 ICI 的原发性耐药可归因于肠道微生物组组成的异常。抗生素抑制了晚期癌症患者对 ICI 的临床获益。来自对 ICI 有反应的癌症患者的粪便微生物群移植（FMT）进入无菌或抗生素处理的小鼠中，改善了 PD-1 阻断的抗肿瘤作用，而来自无反应患者的 FMT 则没有。在诊断时的患者粪便样本的宏基因组学揭示了 ICI 临床反应与相对丰度之间的相关性，口腔补充 在 FMT 后用非反应者粪便恢复了 PD-1 阻断的功效，这是通过增加 CCR9+CXCR3+CD4 T 淋巴细胞募集到小鼠肿瘤床上的方式，以白细胞介素-12 依赖的方式实现的。
