BACKGROUND Assessment of the immune status of muscle-invasive bladder cancer (MIBC) has previously shown to be prognostically relevant after treatment with curative intent. We conducted this study to develop a clinically applicable immune gene expression assay to predict prognosis and adjuvant chemotherapy benefit. PATIENTS AND METHODS Gene expression of CD3Z, CD8A and CXCL9, immune cell (IC) populations including stromal tumor infiltrating lymphocytes (sTILs), T-cells, natural killer cells (NK-cells), macrophages, Programmed cell death protein 1 positive (PD-1) IC and tumor subtypes (MD Anderson Cancer Center/MDACC-approach) were assessed in 187 MIBC patients (Comprehensive Cancer Center Erlangen-EMN/CCC-EMN-cohort). A gene expression signature was derived by hierarchical-clustering and validated in The Cancer Genome Atlas (TCGA)-cohort. IC populations in the TCGA cohort were assessed via CIBERSORT. Benefit of platinum-containing adjuvant chemotherapy was assessed in a pooled cohort of 125 patients. Outcome measurements were disease specific survival, disease-free survival and overall survival. RESULTS The gene expression signature of CXCL9, CD3Z and CD8A correlates with quantitative amounts of specific IC populations and sTILs (CCC-EMN: ρ-range: 0.44-0.74; TCGA: ρ-range: 0.56-0.82) and allows stratification of three different inflammation levels (inflamed high, inflamed low, uninflamed). Highly inflamed tumors are preferentially basal subtype and show favorable 5-year survival rates of 67.3% (HR=0.27; CCC-EMN) and 55% (HR=0.41; TCGA). Uninflamed tumors are predominantly luminal subtypes and show low 5-year survival rates of 28% (CCC-EMN) and 36% (TCGA). Inflamed tumors exhibit higher levels of PD-1 and Programmed cell death 1 ligand 1 (PD-L1). Patients undergoing adjuvant platinum-based chemotherapy with 'inflamed high' tumors showed a favorable 5-year survival rate of 64% (HR=0.27; merged CCC-EMN and TCGA cohort). CONCLUSION The gene expression signature of CD3Z, CD8A and CXCL9 can assess the immune status of MIBC and stratify the survival of MIBC patients undergoing surgery and adjuvant platinum-based chemotherapy. Furthermore, the assay can identify patients with immunological hot tumors with particular high expression of PD-L1 potentially suitable for immunotherapy.

中文翻译：

---

细胞毒性 T 细胞相关基因表达特征预测根治性膀胱切除术和辅助化疗后肌肉浸润性尿路上皮膀胱癌患者的生存率提高。

背景 肌肉浸润性膀胱癌 (MIBC) 免疫状态的评估先前已显示在治愈性治疗后与预后相关。我们进行了这项研究，以开发一种临床适用的免疫基因表达检测方法，以预测预后和辅助化疗获益。患者和方法 CD3Z、CD8A 和 CXCL9、免疫细胞 (IC) 群体的基因表达，包括基质肿瘤浸润淋巴细胞 (sTIL)、T 细胞、自然杀伤细胞 (NK 细胞)、巨噬细胞、程序性细胞死亡蛋白 1 阳性 (PD) -1) 在 187 名 MIBC 患者（综合癌症中心 Erlangen-EMN/CCC-EMN-队列）中评估了 IC 和肿瘤亚型（MD Anderson 癌症中心/MDACC-方法）。基因表达特征是通过分层聚类得出的，并在癌症基因组图谱 (TCGA) 队列中进行了验证。TCGA 队列中的 IC 人群通过 CIBERSORT 进行评估。在 125 名患者的合并队列中评估了含铂辅助化疗的益处。结果测量是疾病特异性生存率、无病生存率和总生存率。结果 CXCL9、CD3Z 和 CD8A 的基因表达特征与特定 IC 群体和 sTIL 的定量相关（CCC-EMN：ρ-范围：0.44-0.74；TCGA：ρ-范围：0.56-0.82）并允许对三种不同炎症水平（高发炎、低发炎、未发炎）。高度发炎的肿瘤优先为基础亚型，并且显示出有利的 5 年生存率，分别为 67.3%（HR=0.27；CCC-EMN）和 55%（HR=0.41；TCGA）。未发炎的肿瘤主要是管腔亚型，5 年生存率较低，分别为 28% (CCC-EMN) 和 36% (TCGA)。发炎的肿瘤表现出更高水平的 PD-1 和程序性细胞死亡 1 配体 1 (PD-L1)。接受铂类辅助化疗的“炎症高”肿瘤患者的 5 年生存率为 64%（HR=0.27；合并 CCC-EMN 和 TCGA 队列）。结论 CD3Z、CD8A和CXCL9的基因表达特征可以评估MIBC的免疫状态，并对接受手术和辅助铂类化疗的MIBC患者的生存进行分层。此外，该测定可以识别具有特别高表达 PD-L1 的免疫热肿瘤患者，这些患者可能适合免疫治疗。合并 CCC-EMN 和 TCGA 队列）。结论 CD3Z、CD8A和CXCL9的基因表达特征可以评估MIBC的免疫状态，并对接受手术和辅助铂类化疗的MIBC患者的生存进行分层。此外，该测定可以识别具有特别高表达 PD-L1 的免疫热肿瘤患者，这些患者可能适合免疫治疗。合并 CCC-EMN 和 TCGA 队列）。结论 CD3Z、CD8A和CXCL9的基因表达特征可以评估MIBC的免疫状态，并对接受手术和辅助铂类化疗的MIBC患者的生存进行分层。此外，该测定可以识别具有特别高表达 PD-L1 的免疫热肿瘤患者，这些患者可能适合免疫治疗。