PO.PR01.04 · 预防研究
人类病毒组及其与晚期非小细胞肺癌患者免疫检查点抑制剂治疗临床获益的关联
The human virome and its association with clinical benefit of immune checkpoint inhibitor therapy among patients with advanced non-small cell lung cancer
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摘要 Abstract
中文摘要
背景。本研究的目的是考察接受免疫检查点抑制剂（ICI）治疗的晚期肺癌患者的人类肠道病毒组，以确定病毒检出模式是否能够预测临床获益。
方法。该队列纳入 66 例 III-IV 期肺癌患者，于 2019 年 6 月至 2 月间招募。入选条件限于计划在 Moffitt 癌症中心接受 ICI 治疗的初治个体。从每位患者首个 ICI 周期前 24-72 小时内采集的粪便中提取 DNA。为生成哺乳动物病毒和细菌病毒（噬菌体）的分类学谱，使用 Bowtie2 版本 2.3.5.1 程序将读段与公开可用的数据库进行比对。采用多变量逻辑回归估计病毒分类单位（OTU）相对丰度与 ICI 临床获益之间的关联。采用随机森林机器学习分析选择一组病毒 OTU，其相对丰度能最准确地将患者分类为 ICI 治疗有/无临床获益。
结果。我们在 34 例接受 ICI 治疗的肺癌患者中观察到临床获益。我们观察到，根据 ICI 临床获益，肺癌患者之间人类肠道病毒组多个组分的相对丰度存在差异。最显著的是在噬菌体（细菌病毒）相对丰度上观察到的差异。我们观察到，在 q<0.05 水平（多重检验校正的 p 值）上，239 种噬菌体在有临床获益与无临床获益的肺癌患者中以不同频率富集。此外，使用 15 种噬菌体的组合可实现 91% 的 ICI 临床获益判别曲线下面积（AUC）。这包括 10 个来自 Siphoviridae 科的 OTU、2 个来自 Myoviridae 科、2 个来自 Podoviridae，以及 1 个来自 Caudoviridales 科。对于这 15 种噬菌体中除一种外的所有噬菌体，我们能够高置信度地识别出作为噬菌体靶标的共识细菌属。其中两种细菌——Ruminococcus 和 Bacteroides——在微生物组研究中一直被认为与 ICI 反应相关。
结论。我们研究的意义不仅在于阐明了影响人类健康和疾病的人类肠道环境的又一组分——噬菌体，还在于确定了其在潜在改变对癌症导向的免疫检查点抑制剂治疗反应中的特定作用。
查看英文原文 English abstract
Background. The goal of this study was to examine the human gut virome in advanced lung cancer patients being treated with immune checkpoint inhibitor (ICI) therapy to determine whether patterns of viral detection could predict clinical benefit.
Methods . This cohort of 66 patients with stage III-IV lung cancer patients was recruited between June and February 2019. Eligibility was limited to treatment-naïve individuals who were scheduled to receive ICI therapy at Moffitt Cancer Center. DNA was extracted from stool collected within 24-72 hours prior to each patient's first ICI cycle. To generate the mammalian virus and bacterial virus (phage) taxonomic profiles, reads were aligned to publicly available databases using program Bowtie2 version 2.3.5.1. Multivariable logistic regression was used to estimate the association between the relative abundance of viral taxonomic units (OTUs) and ICI clinical benefit. Random forest machine learning analysis was used to select a set of viral OTUs whose relative abundance most accurately classified patients as yes/no for clinical benefit of ICI therapy.
Results . We observed clinical benefit in 34 lung cancer patients treated with ICI therapy. We observed differences in the relative abundance of multiple components of the human gut virome between lung cancer patients according to ICI clinical benefit. Most marked were the differences observed in the relative abundance of phages (bacterial viruses). We observed that 239 phages were abundant at different frequencies in lung cancer patients with versus without clinical benefit of ICI therapy at the q<0.05 level (multiple testing corrected p-value). In addition, an area under the curve (AUC) for discrimination of ICI clinical benefit of 91% could be achieved using a 15-phage combination. This included 10 OTUs from the family Siphoviridae , 2 from the family Myoviridae , 2 from Podoviridae , and 1 from family Caudoviridales. For all but one of these 15 phages, we were able to identify a consensus bacterial genus as the phage target with high confidence. Two of these bacteria - Ruminococcus and Bacteroides - have consistently been identified in microbiome studies as being associated with ICI response.
Conclusion . Implications of our research include not just the elucidation of a further component of the human gut environment - phages - that impacts human health and disease, but also the identification of its specific role in potentially altering response to cancer-directed immune checkpoint inhibitor therapy.
利益披露 Disclosure
A. E. Coghill, None..
A. Lazaryan, None..
R. Pollenz, None.