Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors
Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors
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DOI：
10.1126/science.aan3706
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发表时间：
2018-01-05
期刊：
影响因子：
56.9
通讯作者：
Zitvogel, Laurence
中科院分区：
文献类型：
--
作者：
Routy, Bertrand;Le Chatelier, Emmanuelle;Zitvogel, Laurence
靶向PD-1/PD-L1轴的免疫检查点抑制剂（ICI）在相当多的少数癌症患者中诱导持续的临床应答。我们发现，对ICI的原发性耐药性可归因于异常的肠道微生物组组成。抗生素抑制了ICIs在晚期癌症患者中的临床获益。将对ICI有反应的癌症患者的粪便微生物群移植（FMT）到无菌或无菌治疗的小鼠中，改善了PD-1阻断的抗肿瘤作用，而来自无反应患者的FMT则未能做到这一点。诊断时患者粪便样本的宏基因组学揭示了对ICI的临床应答与嗜粘蛋白阿克曼氏菌的相对丰度之间的相关性。口服补充A. FMT后，使用无应答者粪便的嗜粘蛋白菌通过增加CCR 9（+）CXCR 3（+）CD 4（+）T淋巴细胞向小鼠肿瘤床的募集，以白细胞介素-12依赖性方式恢复了PD-1阻断的功效。
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 Akkermansia muciniphila. Oral supplementation with A. muciniphila after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9(+)CXCR3(+)CD4(+) T lymphocytes into mouse tumor beds.