Abstract：
The gut microbiome significantly influences immune responses and the efficacy of immune checkpoint inhibitors. We conducted a clinical trial (NCT04264975) combining an anti-programmed death-1 (PD-1) inhibitor with fecal microbiota transplantation (FMT) from anti-PD-1 responder in 13 patients with anti-PD-1-refractory advanced solid cancers. FMT induced sustained microbiota changes and clinical benefits in 6 of 13 patients, with 1 partial response and 5 stable diseases, achieving an objective response rate of 7.7% and a disease control rate of 46.2%. The clinical response correlates with increased cytotoxic T cells and immune cytokines in blood and tumors. We isolated Prevotella merdae Immunoactis from a responder to FMT, which stimulates T cell activity and suppresses tumor growth in mice by enhancing cytotoxic T cell infiltration. Additionally, we found Lactobacillus salivarius and Bacteroides plebeius may inhibit anti-tumor immunity. Our findings suggest that FMT with beneficial microbiota can overcome resistance to anti-PD-1 inhibitors in advanced solid cancers, especially gastrointestinal cancers.
摘要：
肠道微生物组显着影响免疫应答和免疫检查点抑制剂的功效。我们在13例抗PD-1难治性晚期实体癌患者中进行了一项临床试验（NCT04264975），将抗程序性死亡-1（PD-1）抑制剂与抗PD-1应答者的粪便微生物群移植（FMT）相结合。FMT在13例患者中有6例引起持续的微生物群变化和临床获益，有1个部分反应和5个稳定的疾病，达到7.7%的客观反应率和46.2%的疾病控制率。临床反应与血液和肿瘤中细胞毒性T细胞和免疫细胞因子的增加相关。我们从FMT的应答者中分离出免疫普雷氏菌，通过增强细胞毒性T细胞浸润刺激T细胞活性并抑制小鼠肿瘤生长。此外,我们发现唾液乳杆菌和拟杆菌属可能抑制抗肿瘤免疫。我们的研究结果表明，具有有益微生物群的FMT可以克服晚期实体癌对抗PD-1抑制剂的耐药性，尤其是胃肠道癌症。
