Immune-checkpoint blockades (ICBs) have been routinely implemented to treat metastatic urothelial cancer (mUC), whereas robust biomarkers are urgently warranted. Herein, we explored latent promising biomarkers based on 348 pretreatment mUC samples from IMvigor210./nMethods: The genome, transcriptome, immunome, and metabolome were systemically analyzed using the external TCGA dataset for validation. Kaplan-Meier and ROC curve analyses were performed to estimate the predictive capacity of M1-macrophage infiltration. Chi-square/Spearman/Mann Whitney U test are used to determine its correlation to genetic, biochemical, and clinicopathological parameters./nResults: M1 frequency is a robust biomarker for predicting the prognosis and response to ICBs, which is non-inferior to tumor mutation burden (TMB) or tumor neoantigen burden (TNB), and exceeds CD8 T cells, T cell inflamed gene expression profile (GEP), and PD-L1 expression. Moreover, M1 infiltration is associated with immune phenotypes (AUC = 0.785) and is negatively correlated with immune exclusion. Additionally, transcriptomic analysis showed immune activation in the high-M1 subgroup, whereas it showed steroid and drug metabolism reprograming in the M1-deficient subset, which characterized the limited sensitivity to ICB therapy. Notably, investigation of the corresponding intrinsic genomic profiles highlighted the significance of TP53 and FGFR alterations./nConclusions: M1 infiltration is a robust biomarker for immunotherapeutic response and immunophenotype determination in an mUC setting. Innate immunity activation involving macrophage polarization remodeling and anti-FGFR mutations may be promising strategies for synergy with anti-PD-L1 treatments and may help prolong the clinical survival of patients with mUC.

中文翻译：

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巨噬细胞与免疫表型相关并预测尿路上皮癌的抗 PD-L1 反应。

免疫检查点阻断（ICB）已常规用于治疗转移性尿路上皮癌（mUC），而迫切需要强大的生物标志物。在此，我们基于来自 IMvigor210 的 348 个预处理 mUC 样本探索了潜在有前景的生物标志物。/n方法：使用外部 TCGA 数据集对基因组、转录组、免疫组和代谢组进行系统分析以进行验证。进行 Kaplan-Meier 和 ROC 曲线分析来估计 M1 巨噬细胞浸润的预测能力。卡方/Spearman/Mann Whitney U 检验用于确定其与遗传、生化和临床病理参数的相关性。/n结果： M1 频率是预测 ICB 预后和反应的稳健生物标志物，其不劣于肿瘤突变负荷（TMB）或肿瘤新抗原负荷（TNB），并且超过CD8 T细胞、T细胞炎症基因表达谱（GEP）和PD-L1表达。此外，M1浸润与免疫表型相关（AUC = 0.785），并与免疫排斥呈负相关。此外，转录组分析显示高 M1 亚组中存在免疫激活，而 M1 缺陷亚组中则显示类固醇和药物代谢重新编程，其特点是对 ICB 治疗的敏感性有限。值得注意的是，对相应内在基因组图谱的研究强调了TP53和FGFR改变的重要性。/n结论： M1 浸润是 mUC 环境中免疫治疗反应和免疫表型确定的稳健生物标志物。涉及巨噬细胞极化重塑和抗FGFR突变的先天免疫激活可能是与抗 PD-L1 治疗协同的有前途的策略，并可能有助于延长 mUC 患者的临床生存期。