地址1
盘状结构域
免疫系统
癌症研究
基因签名
危险系数
生物
免疫检查点
基因表达
免疫疗法
肿瘤科
受体酪氨酸激酶
免疫学
内科学
医学
基因
受体
遗传学
置信区间
作者
Sungyong You,Minhyung Kim,Xen Ping Hoi,Yu-Cheng Lee,Li Wang,David Spetzler,Jim Abraham,Dan Magee,Prerna Jain,Matthew D. Galsky,Keith C. C. Chan,Dan Theodorescu
摘要
Abstract Background Anti–programmed cell death 1 (anti–PD-1) and PD ligand 1 (PD-L1) immune checkpoint therapies (ICTs) provided durable responses only in a subset of cancer patients. Thus, biomarkers are needed to predict nonresponders 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 whether this gene family may provide ICT response prediction. Methods We assessed mRNA expression of DDR2 and its family member DDR1. Transcriptome analysis of bladder cancer (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–The Cancer Genome Atlas (n = 259) and IMvigor210 (n = 298) datasets, and their relationship to BCa subtypes, pathway enrichment, and immune deconvolution analyses was performed. The potential of DDR-driven signatures to predict ICT response was 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, whereas DDR1high BCa exhibited a non–T-cell–inflamed phenotype. In IMvigor210 cohort, tumors with high DDR1 (hazard ratio [HR] = 1.53, 95% confidence interval [CI] = 1.16 to 2.06; P = .003) or DDR2 (HR = 1.42, 95% CI = 1.01 to 1.92; P = .04) scores had poor overall survival. Of note, DDR2high tumors from IMvigor210 and CheckMate 275 (n = 73) cohorts exhibited poorer overall survival (HR = 1.56, 95% CI = 1.20 to 2.06; P < .001) and progression-free survival (HR = 1.77 95%, CI = 1.05 to 3.00; P = .047), respectively. This result was validated in independent cancer datasets. Conclusions These findings implicate DDR1 and DDR2 driven signature scores in predicting ICT response.
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