Zhao Zihan, Jiang Ning, Zhang Yulin, Bai Yuhao, Liu Tianyao, Li Tianhang, Guo Hongqian, Yang Rong
Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Institute of Urology, Nanjing University, Nanjing, China.
Department of Urology, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, China.
Front Genet. 2022 Sep 29;13:919829. doi: 10.3389/fgene.2022.919829. eCollection 2022.
Bladder cancer (BLCA) is one of the most common malignant tumors of the urinary system, but the current therapeutic strategy based on chemotherapy and immune checkpoint inhibitor (ICI) therapy cannot meet the treatment needs, mainly owing to the endogenous or acquired apoptotic resistance of cancer cells. Targeting necroptosis provides a novel strategy for chemotherapy and targeted drugs and improves the efficacy of ICIs because of strong immunogenicity of necroptosis. Therefore, we systemically analyzed the necroptosis landscape on therapy and prognosis in BLCA. We first divided BLCA patients from The Cancer Genome Atlas (TCGA) database into two necroptosis-related clusters (C1 and C2). Necroptosis C2 showed a significantly better prognosis than C1, and the differential genes of C2 and C1 were mainly related to the immune response according to GO and KEGG analyses. Next, we constructed a novel necroptosis-related gene (NRG) signature consisting of , , , , , , , and to predict the survival of TCGA-BLCA cohort, and the accuracy of the NRG score was also verified by external datasets. In addition, a nomogram combining NRG score and several clinicopathological features was established to more accurately and conveniently predict the BLCA patient's survival. We also found that the NRG score was significantly related to the infiltration levels of CD8 T cells, NK cells, and iDC cells, the gene expression of CTLA4, PD-1, TIGIT, and LAG3 of TME, and the sensitivity to chemotherapy and targeted agents in BLCA patients. In conclusion, the NRG score has an excellent performance in evaluating the prognosis, clinicopathologic features, tumor microenvironment (TME), and therapeutic sensitivity of BLCA patients, which could be utilized as a guide for chemotherapy, ICI therapy, and combination therapy.
膀胱癌（BLCA）是泌尿系统最常见的恶性肿瘤之一，但目前基于化疗和免疫检查点抑制剂（ICI）治疗的策略无法满足治疗需求，这主要是由于癌细胞存在内源性或获得性凋亡抗性。靶向坏死性凋亡为化疗和靶向药物提供了一种新策略，并且由于坏死性凋亡具有很强的免疫原性，因而能提高ICI的疗效。因此，我们系统分析了膀胱癌中坏死性凋亡格局与治疗及预后的关系。我们首先将来自癌症基因组图谱（TCGA）数据库的膀胱癌患者分为两个与坏死性凋亡相关的簇（C1和C2）。坏死性凋亡C2组的预后明显优于C1组，根据基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析，C2和C1的差异基因主要与免疫反应相关。接下来，我们构建了一个由 、 、 、 、 、 、 和 组成的新型坏死性凋亡相关基因（NRG）特征，以预测TCGA-BLCA队列的生存情况，并且外部数据集也验证了NRG评分的准确性。此外，还建立了一个结合NRG评分和多个临床病理特征的列线图，以更准确、方便地预测膀胱癌患者的生存情况。我们还发现，NRG评分与膀胱癌患者中CD8 T细胞、NK细胞和未成熟树突状细胞（iDC）的浸润水平、肿瘤微环境（TME）中细胞毒性T淋巴细胞相关抗原4（CTLA4）、程序性死亡受体1（PD-1）、T细胞免疫球蛋白和ITIM结构域（TIGIT）以及淋巴细胞活化基因3（LAG3）的基因表达，以及对化疗和靶向药物的敏感性显著相关。总之，NRG评分在评估膀胱癌患者的预后、临床病理特征、肿瘤微环境（TME）和治疗敏感性方面具有优异表现，可作为化疗、ICI治疗及联合治疗的指导依据。
