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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02823-z

摘要内容如下：

针对程序性细胞死亡蛋白1（PD-1）和细胞毒性T淋巴细胞蛋白4（CTLA-4）的免疫检查点阻断（ICB）可以在多种癌症中诱导显著但不可预测的反应。研究表明，癌症患者的肠道微生物群组成与对ICB的临床反应之间存在关系。然而，定义基于微生物的生物标志物来推广整个队列是具有挑战性的。这可能与先前将微生物群量化为物种（或更高分类等级）丰度的努力有关，而微生物功能通常是菌株特异性的。在这里，我们对基线粪便样本进行了深度鸟枪法宏基因组测序，这些样本来自一个独特的、注释丰富的2期试验队列，该队列由接受联合ICB治疗的不同罕见癌症患者组成（n=106个发现队列）。我们证明，相对于使用物种等级量化或综合预处理临床因素建立的模型，菌株分辨的微生物丰度改善了ICB反应和12个月无进展生存期的机器学习预测。通过对另外6项可比较研究（n=364验证队列）的肠道元基因组的荟萃分析，我们发现了应变反应信号的跨癌症（和跨国）有效性，但仅当训练和测试队列使用一致的ICB方案（抗PD-1单药治疗或抗PD-1联合抗CTLA-4）时。这表明，肠道微生物组诊断或治疗的未来发展应根据ICB治疗方案而不是根据癌症类型进行调整。

英文原文如下：

Abstracts

Immune checkpoint blockade (ICB) targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte protein 4 (CTLA-4) can induce remarkable, yet unpredictable, responses across a variety of cancers. Studies suggest that there is a relationship between a cancer patient's gut microbiota composition and clinical response to ICB; however, defining microbiome-based biomarkers that generalize across cohorts has been challenging. This may relate to previous efforts quantifying microbiota to species (or higher taxonomic rank) abundances, whereas microbial functions are often strain specific. Here, we performed deep shotgun metagenomic sequencing of baseline fecal samples from a unique, richly annotated phase 2 trial cohort of patients with diverse rare cancers treated with combination ICB (n = 106 discovery cohort). We demonstrate that strain-resolved microbial abundances improve machine learning predictions of ICB response and 12-month progression-free survival relative to models built using species-rank quantifications or comprehensive pretreatment clinical factors. Through a meta-analysis of gut metagenomes from a further six comparable studies (n = 364 validation cohort), we found cross-cancer (and cross-country) validity of strain-response signatures, but only when the training and test cohorts used concordant ICB regimens (anti-PD-1 monotherapy or combination anti-PD-1 plus anti-CTLA-4). This suggests that future development of gut microbiome diagnostics or therapeutics should be tailored according to ICB treatment regimen rather than according to cancer type.

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