Effects of gut microbiota on immune checkpoint inhibitors in multi-cancer and as microbial biomarkers for predicting therapeutic response.

IF 12.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Med Pub Date : 2024-10-29 DOI:10.1016/j.medj.2024.10.007

Yufeng Lin, Mingxu Xie, Harry Cheuk-Hay Lau, Ruijie Zeng, Ruyi Zhang, Luyao Wang, Qing Li, Yiwei Wang, Danyu Chen, Lanping Jiang, William Damsky, Jun Yu

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引用次数: 0

Abstract

Background: Gut bacteria are related to immune checkpoint inhibitors (ICIs). However, there is inconsistency in ICI-associated species, while the role of non-bacterial microbes in immunotherapy remains elusive. Here, we evaluated the association of trans-kingdom microbes with ICIs by multi-cohort multi-cancer analyses.

Methods: We retrieved fecal metagenomes from 1,359 ICI recipients with four different cancers (metastatic melanoma [MM], non-small cell lung carcinoma [NSCLC], renal cell cancer [RCC], and hepatocellular carcinoma) from 12 published datasets. Microbiota composition was analyzed using the Wilcoxon rank test. The performance of microbial biomarkers in predicting ICI response was assessed by random forest. Key responder-associated microbes were functionally examined in vitro and in mice.

Findings: Trans-kingdom gut microbiota (bacteria, eukaryotes, viruses, and archaea) was significantly different between ICI responders and non-responders in multi-cancer. Bacteria (Faecalibacterium prausnitzii, Coprococcus comes) and eukaryotes (Nemania serpens, Hyphopichia pseudoburtonii) were consistently enriched in responders of ≥2 cancer types or from ≥3 cohorts, contrasting with the depleted bacterium Hungatella hathewayi. Responder-associated species in each cancer were revealed, such as F. prausnitzii in MM and 6 species in NSCLC. These signature species influenced ICI efficacy by modulating CD8⁺ T cell activity in vitro and in mice. Moreover, bacterial and eukaryotic biomarkers showed great performance in predicting ICI response in patients from discovery and two validation cohorts (MM: area under the receiver operating characteristic curve [AUROC] = 72.27%-80.19%; NSCLC: AUROC = 72.70%-87.98%; RCC: AUROC = 83.33%-89.58%).

Conclusions: This study identified trans-kingdom microbial signatures associated with ICI in multi-cancer and specific cancer types. Trans-kingdom microbial biomarkers are potential predictors of ICI response in patients with cancer.

Funding: Funding information is shown in the acknowledgments.

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肠道微生物群对多发性癌症免疫检查点抑制剂的影响以及作为预测治疗反应的微生物生物标记物。

背景：肠道细菌与免疫检查点抑制剂（ICIs）有关。然而，与 ICI 相关的物种并不一致，而非细菌微生物在免疫疗法中的作用仍然难以捉摸。在此，我们通过多队列多癌症分析评估了跨王国微生物与 ICIs 的关联：我们从12个已发表的数据集中检索了1359名患有四种不同癌症（转移性黑色素瘤[MM]、非小细胞肺癌[NSCLC]、肾细胞癌[RCC]和肝细胞癌）的ICI受者的粪便元基因组。微生物群组成采用 Wilcoxon 秩检验进行分析。微生物生物标志物在预测 ICI 反应方面的性能由随机森林进行评估。在体外和小鼠体内对关键的应答者相关微生物进行了功能检测：跨王国肠道微生物群（细菌、真核生物、病毒和古细菌）在多发性癌症的 ICI 反应者和非反应者之间存在显著差异。细菌（Faecalibacterium prausnitzii、Coprococcus comes）和真核生物（Nemania serpens、Hyphopichia pseudoburtonii）在≥2种癌症类型或来自≥3个队列的应答者中持续富集，与贫乏的Hungatella hathewayi细菌形成对比。每种癌症中都发现了与应答者相关的菌种，如 MM 中的 F. prausnitzii 和 NSCLC 中的 6 种菌种。这些特征物种通过调节体外和小鼠体内 CD8+ T 细胞的活性来影响 ICI 的疗效。此外，细菌和真核生物标志物在预测发现组和两个验证组患者的 ICI 反应方面表现出色（MM：接收者操作特征曲线下面积 [AUROC] = 72.27%-80.19%；NSCLC：接收者操作特征曲线下面积 [AUROC] = 72.70%-80.19%；NSCLC：接收者操作特征曲线下面积 [AUROC] = 72.70%-80.19%）：AUROC=72.70%-87.98%；RCC：AUROC=83.33%-89.58%）：本研究发现了与多发性癌症和特定癌症类型的 ICI 相关的跨王国微生物特征。跨王国微生物生物标志物是癌症患者对 ICI 反应的潜在预测因子：资助信息见致谢。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

期刊介绍： Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically. Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.