Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
CytoReason.
Gut. 2019 Apr;68(4):604-614. doi: 10.1136/gutjnl-2017-315494. Epub 2018 Apr 4.
Although anti-tumour necrosis factor alpha (anti-TNFα) therapies represent a major breakthrough in IBD therapy, their cost-benefit ratio is hampered by an overall 30% non-response rate, adverse side effects and high costs. Thus, finding predictive biomarkers of non-response prior to commencing anti-TNFα therapy is of high value.
We analysed publicly available whole-genome expression profiles of colon biopsies obtained from multiple cohorts of patients with IBD using a combined computational deconvolution-meta-analysis paradigm which allows to estimate immune cell contribution to the measured expression and capture differential regulatory programmes otherwise masked due to variation in cellular composition. Insights from this in silico approach were experimentally validated in biopsies and blood samples of three independent test cohorts.
We found the proportion of plasma cells as a robust pretreatment biomarker of non-response to therapy, which we validated in two independent cohorts of immune-stained colon biopsies, where a plasma cellular score from inflamed biopsies was predictive of non-response with an area under the curve (AUC) of 82%. Meta-analysis of the cell proportion-adjusted gene expression data suggested that an increase in inflammatory macrophages in anti-TNFα non-responding individuals is associated with the upregulation of the triggering receptor expressed on myeloid cells 1 (TREM-1) and chemokine receptor type 2 (CCR2)-chemokine ligand 7 (CCL7) -axes. Blood gene expression analysis of an independent cohort, identified TREM-1 downregulation in non-responders at baseline, which was predictive of response with an AUC of 94%.
Our study proposes two clinically feasible assays, one in biopsy and one in blood, for predicting non-response to anti-TNFα therapy prior to initiation of treatment. Moreover, it suggests that mechanism-driven novel drugs for non-responders should be developed.
尽管抗肿瘤坏死因子α（anti-TNFα）疗法代表了 IBD 治疗的重大突破，但由于总体 30%的无应答率、不良反应和高成本，其成本效益比受到阻碍。因此，在开始使用抗 TNFα 治疗之前，寻找无应答的预测生物标志物具有重要价值。
我们使用一种组合的计算去卷积-荟萃分析方法分析了来自多个 IBD 患者队列的结肠活检的公开全基因组表达谱，该方法允许估计免疫细胞对测量表达的贡献，并捕获由于细胞组成变化而掩盖的差异调节程序。这种计算机方法的见解在三个独立测试队列的活检和血液样本中进行了实验验证。
我们发现浆细胞比例是治疗无应答的可靠预处理生物标志物，我们在两个独立的免疫染色结肠活检队列中进行了验证，其中来自炎症性活检的浆细胞评分可预测无应答，曲线下面积（AUC）为 82%。对细胞比例调整后的基因表达数据进行荟萃分析表明，在抗 TNFα 无应答者中，炎症性巨噬细胞的增加与髓样细胞表达的触发受体 1（TREM-1）和趋化因子受体 2（CCR2）-趋化因子配体 7（CCL7）轴的上调有关。对一个独立队列的血液基因表达分析表明，无应答者在基线时 TREM-1 的下调可预测应答，AUC 为 94%。
我们的研究提出了两种临床上可行的检测方法，一种在活检中，一种在血液中，用于在开始治疗前预测对抗 TNFα 治疗的无应答。此外，它表明应开发针对无应答者的基于机制的新型药物。
