美国队列中与免疫检查点 PD-1 阻断治疗反应相关的细菌属的相互作用。
Interaction of bacterial genera associated with therapeutic response to immune checkpoint PD-1 blockade in a United States cohort.
机构信息
Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA.
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
出版信息
Genome Med. 2022 Mar 29;14(1):35. doi: 10.1186/s13073-022-01037-7.
BACKGROUND
Recent studies show that human gut microbial composition can determine whether a patient is a responder or non-responder to immunotherapy but have not identified a common microbial signal shared by responding patients. The functional relationship between immunity, intestinal microbiota, and NSCLC response to immune checkpoint inhibitor/inhibition (ICI) in an American cohort remains unexplored.
METHODS
RNAlater-preserved fecal samples were collected from 65 pre-treatment (baseline) and post-treatment stage III/IV NSCLC patients undergoing ICI therapy, categorized as responders or non-responders according to RECIST criteria. Pooled and individual responder and non-responder microbiota were transplanted into a gnotobiotic mouse model of lung cancer and treated with ICIs. 16S rDNA and RNA sequencing was performed on patient fecal samples, 16S rDNA sequencing on mouse fecal samples, and flow cytometric analysis on mouse tumor tissue.
RESULTS
Responder patients have both a different microbial community structure than non-responders (P = 0.004) and a different bacterial transcriptome (PC2 = 0.03) at baseline. Taxa significantly enriched in responders include amplicon sequence variants (ASVs) belonging to the genera Ruminococcus, Akkermansia, and Faecalibacterium. Pooled and individual responder microbiota transplantation into gnotobiotic mice decreased tumor growth compared to non-responder colonized mice following ICI (P = 0.023, P = 0.019, P = 0.008, respectively). Responder tumors showed an increased anti-tumor cellular phenotype following ICI treatment. Responder mice are enriched with ASVs belonging to the genera Bacteroides, Blautia, Akkermansia, and Faecalibacterium. Overlapping taxa mapping between human and mouse cohorts correlated with tumor size and weight revealed a network highlighting responder-associated ASVs belonging to the genera Colidextribacter, Frisingicoccus, Marvinbryantia, and Blautia which have not yet been reported.
CONCLUSIONS
The role of isolate-specific function and bacterial gene expression in gut microbial-driven responsiveness to ICI has been underappreciated. This work supports further investigation using isolate-driven models to characterize the mechanisms underlying this phenomenon.
背景
最近的研究表明，人类肠道微生物组成可以决定患者对免疫治疗是有反应还是无反应，但尚未确定反应患者共有的常见微生物信号。在一个美国队列中，免疫、肠道微生物群与非小细胞肺癌（NSCLC）对免疫检查点抑制剂/抑制（ICI）反应之间的功能关系仍未得到探索。
方法
从 65 名接受 ICI 治疗的 III/IV 期 NSCLC 患者的预处理（基线）和治疗后阶段采集 RNAlater 保存的粪便样本，根据 RECIST 标准将其分为有反应者和无反应者。将汇集的和个体有反应者和无反应者的微生物群移植到肺癌的无菌小鼠模型中，并接受 ICI 治疗。对患者粪便样本进行 16S rDNA 和 RNA 测序，对小鼠粪便样本进行 16S rDNA 测序，对小鼠肿瘤组织进行流式细胞术分析。
结果
与无反应者相比，有反应者的基线时不仅具有不同的微生物群落结构（P=0.004），而且具有不同的细菌转录组（PC2=0.03）。在有反应者中丰富的分类群包括属于 Ruminococcus、Akkermansia 和 Faecalibacterium 属的扩增子序列变异（ASV）。与无反应者定植的小鼠相比，汇集的和个体的有反应者微生物群移植到无菌小鼠中后，肿瘤生长减少（分别为 P=0.023、P=0.019、P=0.008）。ICI 治疗后，有反应者肿瘤表现出增加的抗肿瘤细胞表型。有反应者小鼠富集的 ASV 属于 Bacteroides、Blautia、Akkermansia 和 Faecalibacterium 属。人类和小鼠队列之间重叠的分类群映射与肿瘤大小和重量相关，揭示了一个突出有反应者相关 ASV 的网络，这些 ASV 属于 Colidextribacter、Frisingicoccus、Marvinbryantia 和 Blautia 属，尚未有报道。
结论
肠道微生物驱动对 ICI 的反应性中，分离株特异性功能和细菌基因表达的作用尚未得到充分认识。这项工作支持使用分离株驱动模型进一步研究，以表征这种现象的机制。
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