Department of Urology, The Second Xiangya Hospital, Central South University, Renmin Middle Road 139, Changsha, 410011, China.
Sci Rep. 2022 May 31;12(1):9066. doi: 10.1038/s41598-022-12712-5.
The role of ferroptosis in tumor development and therapy has been previously proved. Nonetheless, its potential role in tumor microenvironment (TME) and immunotherapy for bladder carcinoma remains unclear. Based on 38 ferroptosis-related genes, the characteristic of ferroptosis patterns and interactions with immune cell-infiltrating features in 2043 bladder cancer samples were systematically investigated. We further proposed the FerrScore to quantify the ferroptosis patterns for each patient. As results, three diverse ferroptosis patterns with distinct tumor-infiltrating immune cell features were established. By determination of ferroptosis patterns of each patient, we found that high FerrScore was related to lower proportion of luminal-papillary molecular subtype, more frequent TP53 mutations, activation of immunity and stroma, and lower 5-year survival. High FerrScore also seemed to be associated with decreased neoantigen load, tumor mutational burden and poorer response to anti-PD-L1/1 therapy. External verification in two immunotherapy cohorts showed FerrScore was an independent and effective prognostic factor for therapeutic effect and survival outcome. Overall, the present study indicated the ferroptosis strongly is closely correlated with TME diversity. Evaluation of the ferroptosis patterns may strengthen the cognition of TME immune cell infiltrations and guide more individualized immunotherapeutic strategies in bladder carcinoma.
铁死亡在肿瘤发展和治疗中的作用此前已得到证实。然而，其在膀胱癌肿瘤微环境（TME）和免疫治疗中的潜在作用尚不清楚。本研究基于 38 个铁死亡相关基因，系统研究了 2043 例膀胱癌样本中与铁死亡模式特征及其与免疫细胞浸润特征的相互作用。我们进一步提出了 FerrScore 来量化每个患者的铁死亡模式。结果，建立了三种不同的铁死亡模式，具有不同的肿瘤浸润免疫细胞特征。通过确定每个患者的铁死亡模式，我们发现高 FerrScore 与腔面-乳头分子亚型的比例较低、TP53 突变更频繁、免疫和基质激活以及 5 年生存率较低有关。高 FerrScore 似乎还与较低的新抗原负荷、肿瘤突变负担和对抗 PD-L1/1 治疗的反应较差有关。在两个免疫治疗队列中的外部验证表明，FerrScore 是治疗效果和生存结果的独立且有效的预后因素。总的来说，本研究表明铁死亡与 TME 的异质性密切相关。评估铁死亡模式可能会加强对 TME 免疫细胞浸润的认识，并指导膀胱癌更个体化的免疫治疗策略。
