Gut microbiome impacts response to PD-1 immunotherapy in melanoma patients

Pre-clinical mouse models have suggested that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy, however this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing PD-1 blockade immunotherapy (n=112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders (R) versus non-responders (NR). Analysis of patient fecal microbiome samples (n=43, 30R, 13NR) showed significantly higher alpha diversity (p<0.01) and relative abundance of Ruminococcaceae bacteria (p<0.01) in R. Metagenomic studies revealed functional differences in gut bacteria in R including enrichment of anabolic pathways. Immune profiling found enhanced systemic and anti-tumor immunity in responding patients with a favorable gut microbiome, as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for treatment with immune checkpoint blockade in melanoma.

临床前小鼠模型研究提示，肠道微生物组可调控肿瘤对免疫检查点阻断免疫治疗的应答反应，但目前针对人类癌症患者的相关特征性分析仍较为匮乏。本研究针对112例接受PD-1阻断免疫治疗的黑色素瘤患者，对其口腔及肠道微生物组展开了分析。应答者（R）与无应答者（NR）的肠道微生物组多样性及组成均存在显著差异。对43例患者的粪便微生物组样本（其中应答者30例、无应答者13例）进行分析后发现，应答者的肠道微生物组α多样性显著更高（p<0.01），且瘤胃球菌科（Ruminococcaceae）细菌的相对丰度亦显著升高（p<0.01）。宏基因组学分析显示，应答者的肠道细菌存在功能层面的差异，具体表现为合成代谢通路的富集。免疫特征分析显示，肠道微生物组状态良好的应答患者，以及接受应答者粪便移植的无菌小鼠，均呈现出增强的系统性免疫与抗肿瘤免疫活性。综上，本研究数据为黑色素瘤的免疫检查点阻断治疗提供了重要的理论参考与临床指导价值。