Department of Pathology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226006, China.
Department of Occupational Medicine and Environmental Toxicology, Nantong Key Laboratory of Environmental Toxicology, School of Public Health, Nantong University, Nantong, 226019, China.
BMC Cancer. 2024 Aug 26;24(1):1046. doi: 10.1186/s12885-024-12820-7.
Immune checkpoint inhibitors (ICIs) are rapidly evolving in the management of bladder cancer (BLCA). Nevertheless, effective biomarkers for predicting immunotherapeutic outcomes in BLCA are still insufficient. Ferroptosis, a form of immunogenic cell death, has been found to enhance patient sensitivity to ICIs. However, the underlying mechanisms of ferroptosis in promoting immunotherapy efficacy in BLCA remain obscure.
Our analysis of The Cancer Genome Atlas (TCGA) mRNA data using single sample Gene Set Enrichment Analysis (ssGSEA) revealed two immunologically distinct subtypes. Based on these subtypes and various other public cohorts, we identified Apolipoprotein L6 (APOL6) as a biomarker predicting the efficacy of ICIs and explored its immunological correlation and predictive value for treatment. Furthermore, the role of APOL6 in promoting ferroptosis and its mechanism in regulating this process were experimentally validated.
The results indicate that APOL6 has significant immunological relevance and is indicative of immunologically hot tumors in BLCA and many other cancers. APOL6, interacting with acyl-coenzyme A synthetase long-chain family member 4 (ACSL4), mediates immunotherapy efficacy by ferroptosis. Additionally, APOL6 is regulated by signal transducer and activator of transcription 1 (STAT1).
To conclude, our findings indicate APOL6 has potential as a predictive biomarker for immunotherapy treatment success estimation and reveal the STAT1/APOL6/GPX4 axis as a critical regulatory mechanism in BLCA.
免疫检查点抑制剂（ICIs）在膀胱癌（BLCA）的治疗中迅速发展。然而，用于预测 BLCA 免疫治疗结果的有效生物标志物仍然不足。铁死亡是一种免疫原性细胞死亡形式，已被发现可增强患者对 ICI 的敏感性。然而，铁死亡在促进 BLCA 免疫治疗疗效中的潜在机制仍不清楚。
我们使用单样本基因集富集分析（ssGSEA）对癌症基因组图谱（TCGA）mRNA 数据进行分析，发现了两种免疫上不同的亚型。基于这些亚型和各种其他公共队列，我们确定载脂蛋白 L6（APOL6）是预测 ICI 疗效的生物标志物，并探索了其免疫相关性及其对治疗的预测价值。此外，还通过实验验证了 APOL6 在促进铁死亡中的作用及其在调节该过程中的机制。
结果表明，APOL6 具有显著的免疫学相关性，是 BLCA 和许多其他癌症中免疫热肿瘤的标志物。APOL6 与酰基辅酶 A 合成酶长链家族成员 4（ACSL4）相互作用，通过铁死亡介导免疫治疗疗效。此外，APOL6 受信号转导和转录激活因子 1（STAT1）调控。
综上所述，我们的研究结果表明，APOL6 可能是预测免疫治疗治疗效果的生物标志物，并揭示了 STAT1/APOL6/GPX4 轴作为 BLCA 中关键调节机制的潜力。
