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Discoidin domain receptor-driven gene signatures as markers of patient response to anti-PD-L1 immune checkpoint therapy
Journal of the National Cancer Institute ( IF 10.3 ) Pub Date : 2022-08-03 , DOI: 10.1093/jnci/djac140
Sungyong You, Minhyung Kim, Xen Ping Hoi, Yu Cheng Lee, Li Wang, David Spetzler, Jim Abraham, Dan Magee, Prerna Jain, Matthew D Galsky, Keith Syson Chan, Dan Theodorescu

Background Anti-PD-1/PD-L1 immune checkpoint therapies (ICTs) only provided durable responses in a subset of cancer patients. Thus, biomarkers are needed to predict non-responders and offer them alternative treatments. We recently implicated discoidin domain receptor tyrosine kinase 2 (DDR2) as a contributor to anti-PD-1 resistance in animal models; therefore, we sought to investigate if this gene family may provide ICT response prediction. Methods We assessed mRNA expression of DDR2 and its family member DDR1. Transcriptome analysis of BCa models in which DDR1 and 2 were perturbed was used to derive DDR1- and DDR2-driven signature scores. DDR mRNA expression and gene signature scores were evaluated using BCa TCGA (n = 259) and IMvigor210 (n = 298) datasets, and their relationship to BCa subtypes, pathway enrichment, and immune deconvolution analyses were performed. The potential of DDR-driven signatures to predict ICT response were evaluated and independently validated through a statistical framework in bladder and lung cancer cohorts. All statistical tests were 2-sided. Results DDR1 and DDR2 showed mutually exclusive gene expression patterns in human tumors. DDR2high BCa exhibited activation of immune pathways and a high “immune score”, indicative of a T-cell-inflamed phenotype, while DDR1high BCa exhibited a non-T-cell-inflamed phenotype. In IMvigor210 cohort, tumors with high DDR1 (HR = 1.53 95% CI = [1.16–2.06], P=.003) or DDR2 (HR = 1.42 95% CI = [1.01–1.92], P=.04) scores had poor overall survival (OS). Of note, DDR2high tumors from IMvigor210 and CheckMate 275 (n = 73) cohorts exhibited poorer OS (HR = 1.56 95% CI = [1.20–2.06], P<.001) and progression-free survival (HR = 1.77 95% CI = [1.05–3.00], P=.047), respectively. This was validated in independent cancer datasets. Conclusions These findings implicate DDR1/2-driven signature scores in predicting ICT response.

中文翻译:

盘状蛋白结构域受体驱动的基因特征作为患者对抗 PD-L1 免疫检查点治疗反应的标志物

背景 抗 PD-1/PD-L1 免疫检查点疗法 (ICT) 仅在一部分癌症患者中提供持久的缓解。因此,需要生物标志物来预测无反应者并为他们提供替代治疗。我们最近发现盘状结构域受体酪氨酸激酶 2 (DDR2) 是动物模型中抗 PD-1 耐药性的一个贡献者;因此,我们试图研究该基因家族是否可以提供 ICT 反应预测。方法 我们评估了 DDR2 及其家族成员 DDR1 的 mRNA 表达。对 DDR1 和 2 受到干扰的 BCa 模型进行转录组分析,用于得出 DDR1 和 DDR2 驱动的特征分数。使用 BCa TCGA (n = 259) 和 IMvigor210 (n = 298) 数据集评估 DDR mRNA 表达和基因特征评分,并进行它们与 BCa 亚型、通路富集和免疫反卷积分析的关系。通过膀胱癌和肺癌队列的统计框架,对 DDR 驱动的特征预测 ICT 反应的潜力进行了评估和独立验证。所有统计检验都是双面的。结果 DDR1 和 DDR2 在人类肿瘤中表现出相互排斥的基因表达模式。DDR2high BCa 表现出免疫途径激活和高“免疫评分”,表明 T 细胞炎症表型,而 DDR1high BCa 表现出非 T 细胞炎症表型。在 IMvigor210 队列中,具有高 DDR1 (HR = 1.53 95% CI = [1.16–2.06], P=.003) 或 DDR2 (HR = 1.42 95% CI = [1.01–1.92], P=.04) 评分的肿瘤具有较高的评分总生存期 (OS) 较差。值得注意的是,来自 IMvigor210 和 CheckMate 275 (n = 73) 队列的 DDR2high 肿瘤表现出较差的 OS (HR = 1.56 95% CI = [1.20–2.06], P<.001) 和无进展生存期 (HR = 1.77 95% CI) = [1.05–3.00],P=.047)。这在独立的癌症数据集中得到了验证。结论 这些发现表明 DDR1/2 驱动的特征分数可以预测 ICT 响应。
更新日期:2022-08-03
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