Table_1_Biomarkers of the Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma.DOCX

The mechanisms underlying the resistance to immune checkpoint inhibitors (ICIs) therapy in metastatic urothelial carcinoma (mUC) patients are not clear. It is of great significance to discern mUC patients who could benefit from ICI therapy in clinical practice. In this study, we performed machine learning method and selected 10 prognostic genes for constructing the immunotherapy response nomogram for mUC patients. The calibration plot suggested that the nomogram had an optimal agreement with actual observations when predicting the 1- and 1.5-year survival probabilities. The prognostic nomogram had a favorable discrimination of overall survival of mUC patients, with area under the curve values of 0.815, 0.752, and 0.805 for ICI response (ICIR) prediction in the training cohort, testing cohort, and combined cohort, respectively. A further decision curve analysis showed that the prognostic nomogram was superior to either mutation burden or neoantigen burden for overall survival prediction when the threshold probability was >0.35. The immune infiltrate analysis indicated that the low ICIR-Score values in mUC patients were significantly related to CD8+ T cell infiltration and immune checkpoint-associated signatures. We also identified differentially mutated genes, which could act as driver genes and regulate the response to ICI therapy. In conclusion, we developed and validated an immunotherapy-responsive nomogram for mUC patients, which could be conveniently used for the estimate of ICI response and the prediction of overall survival probability for mUC patients.

关于转移性尿路上皮癌（mUC）患者对免疫检查点抑制剂（ICIs）疗法产生抗性的机制尚不明确。在临床实践中，甄别可能从ICIs疗法中获益的mUC患者具有重要意义。本研究中，我们运用机器学习方法，选定了10个预后基因，构建了针对mUC患者的免疫疗法反应列线图。校准图表明，该列线图在预测1年和1.5年生存概率时，与实际观察结果具有最佳的一致性。预后列线图在区分mUC患者的总生存期方面表现出良好的区分能力，其曲线下面积值分别为0.815、0.752和0.805，分别对应于训练队列、测试队列和合并队列中的免疫检查点反应（ICIR）预测。进一步的决策曲线分析显示，当阈值概率大于0.35时，该预后列线图在总生存期预测方面优于突变负荷或新抗原负荷。免疫浸润分析表明，mUC患者中低ICIR-Score值与CD8+ T细胞浸润和免疫检查点相关标志物显著相关。我们还确定了差异突变基因，这些基因可能作为驱动基因，调节对ICIs疗法的反应。总之，我们开发并验证了一种针对mUC患者的免疫疗法反应列线图，该图可方便地用于估计ICIs反应和预测mUC患者的总生存期概率。