An immune relevant signature for predicting prognoses and immunotherapeutic responses in patients with muscle-invasive bladder cancer (MIBC)
An immune relevant signature for predicting prognoses and immunotherapeutic responses in patients with muscle-invasive bladder cancer (MIBC)
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DOI：
10.1002/cam4.2942
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发表时间：
2020-02-25
期刊：
影响因子：
4
通讯作者：
Zhu, Yu
中科院分区：
文献类型：
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作者：
Jiang, Wen;Zhu, Dandan;Zhu, Yu
免疫检查点抑制剂（ICIs）是显着改善 MIBC 患者生存时间的新型治疗方法，但 MIBC 患者之间的免疫治疗反应不同。因此，迫切需要找到能够准确识别对 ICI 敏感的 MIBC 患者的预测生物标志物。在本研究中，我们使用单样本基因集富集分析 (ssGSEA) 根据 MIBC 患者的表达谱计算了 24 种免疫细胞的相对丰度。对 24 种免疫细胞进行无监督聚类分析，将 MIBC 患者分为不同的免疫浸润组。不同免疫浸润组之间的基因组（基因突变和拷贝数变异）、转录组（mRNA、lncRNA 和 miRNA）和功能富集存在异质性。我们通过比较具有不同免疫浸润特征的患者的表达谱，鉴定了 282 个与免疫浸润相关的差异表达基因（DEG），并通过单变量 Cox 回归分析鉴定了 20 个核心预后 DEG。使用最小绝对收缩和选择算子 (LASSO) Cox 回归分析构建了由九个关键预后 DEG（CCDC80、CD3D、CIITA、FN1、GBP4、GNLY、SPINK1、UBD 和 VIM）组成的免疫相关基因特征（TIM 特征）。受试者工作特征（ROC）曲线和亚组分析证实，TIM 特征是预测 MIBC 患者预后的理想生物标志物。其预测免疫治疗反应的价值也在癌症基因组图谱 (TCGA) 队列（AUC = 0.69，95% CI = 0.63-0.74）和 IMvigor210 队列（AUC = 0.64，95% = 0.55-0.74）中得到验证。 TIM 特征显示出区分具有不同预后和免疫治疗反应的 MIBC 患者的强大能力，但未来需要更多前瞻性研究来评估其可靠性。
Immune checkpoint inhibitors (ICIs) are novel treatments that significantly improve the survival time of MIBC patients, but immunotherapeutic responses are different among MIBC patients. Therefore, it is urgent to find predictive biomarkers that can accurately identify MIBC patients who are sensitive to ICIs. In this study, we computed the relative abundances of 24 immune cells based on the expression profiles of MIBC patients using single-sample gene set enrichment analysis (ssGSEA). Unsupervised clustering analysis of the 24 immune cells was performed to classify MIBC patients into different immune-infiltrating groups. Genome (gene mutation and copy number variation), transcriptome (mRNA, lncRNA, and miRNA), and functional enrichment were found to be heterogeneous among different immune-infiltrating groups. We identified 282 differentially expressed genes (DEGs) associated with immune infiltration by comparing the expression profiles of patients with different immune infiltration profiles, and 20 core prognostic DEGs were identified by univariate Cox regression analysis. An immune-relevant gene signature (TIM signature) consisting of nine key prognostic DEGs (CCDC80, CD3D, CIITA, FN1, GBP4, GNLY, SPINK1, UBD, and VIM) was constructed using least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Receiver operating characteristic (ROC) curves and subgroup analysis confirmed that the TIM signature was an ideal biomarker for predicting the prognosis of MIBC patients. Its value in predicting immunotherapeutic responses was also validated in The Cancer Genome Atlas (TCGA) cohort (AUC = 0.69, 95% CI = 0.63-0.74) and the IMvigor210 cohort (AUC = 0.64, 95% = 0.55-0.74). The TIM signature demonstrates a powerful ability to distinguish MIBC patients with different prognoses and immunotherapeutic responses, but more prospective studies are needed to assess its reliability in the future.