Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Engineering Research Center for Bladder Tumor Innovation Diagnosis and Treatment, Hangzhou, China.
Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Engineering Research Center for Bladder Tumor Innovation Diagnosis and Treatment, Hangzhou, China.
Surgery. 2024 Sep;176(3):785-797. doi: 10.1016/j.surg.2024.04.027. Epub 2024 Jun 8.
Advanced clear cell renal cell carcinoma still lacks reliable diagnostic and prognostic biomarkers. Recently, tumor vaccines targeting specific molecules have been proposed as a promising treatment in mitigating tumor progression, which was rekindled under the background of the COVID-19 pandemic. However, the application of messenger RNA vaccine against advanced clear cell renal cell carcinoma antigens remains stagnant, and no subgroup of patients deemed suitable for vaccination has been extensively studied or validated. Our study aims to explore novel advanced clear cell renal cell carcinoma antigen signatures to select suitable patients for vaccination.
Gene expression profiles of advanced clear cell renal cell carcinoma samples and their corresponding clinical data were retrieved from The Cancer Genome Atlas. The least absolute shrinkage and selection operator model was applied to develop signatures to stratify patients with advanced clear cell renal cell carcinoma. Receiver operating characteristic analysis was used to compare the prognostic accuracy of each factor. Tumor Immune Estimation Resource was used to visualize the relationship between the proportion of antigen-presenting cells and the expression of filtered genes. The "CIBERSORT" and "WGCNA" R Packages were employed to ascertain disparities in immune infiltration levels between advanced clear cell renal cell carcinoma subgroups. The Search Tools for the Retrieval of Interacting Genes database and Cytoscape were used to construct the protein-protein interaction network. CCK-8 and colony formation assays were included in the invitro experiment.
In total, 244 potential tumor antigens were identified. Using the least absolute shrinkage and selection operator Cox regression, 21 tumor antigens were selected for developing a risk evaluation signature. The risk score signature can be a useful tool to predict the outcome of advanced clear cell renal cell carcinoma patients. According to the differential clinical, molecular, and immune-related genes, we divided advanced clear cell renal cell carcinoma patients into the immune "cold" subtype and immune "hot" subtype. By developing a logistic score, the immune subtype signature can better distinguish a patient more likely to be immune "cold" subtype or immune "hot" subtype. Interestingly, patients with high risk scores had a higher proportion of immune "hot" subtype than those with a low risk score. Furthermore, the prognostic value was significantly improved when combining risk score and immune subtype. Distinct immune landscapes and signal pathways were observed between different tumor subtypes. Finally, novel tumor antigens related to oxidative stress were identified.
The tumor-antigens-based risk score and immune subtype signatures identified potentially effective neo-antigens for advanced clear cell renal cell carcinoma messenger RNA vaccine development, and patients with low risk scores and immune "cold" subtype tumors are more prone to benefit from messenger RNA vaccination. Furthermore, our study highlights the significant role of oxidative stress in determining the efficacy of the messenger RNA vaccine.
高级透明细胞肾细胞癌仍然缺乏可靠的诊断和预后生物标志物。最近，针对特定分子的肿瘤疫苗作为一种有前途的治疗方法被提出，可以减轻肿瘤的进展，这在 COVID-19 大流行的背景下重新燃起了希望。然而，信使 RNA 疫苗针对高级透明细胞肾细胞癌抗原的应用仍然停滞不前，并且没有广泛研究或验证适合接种疫苗的亚组患者。我们的研究旨在探索新型高级透明细胞肾细胞癌抗原标志物，以选择适合接种疫苗的患者。
从癌症基因组图谱中检索高级透明细胞肾细胞癌样本的基因表达谱及其相应的临床数据。应用最小绝对收缩和选择算子模型开发标志物对高级透明细胞肾细胞癌患者进行分层。接收器操作特性分析用于比较每个因素的预后准确性。肿瘤免疫估计资源用于可视化抗原呈递细胞比例与筛选基因表达之间的关系。使用“CIBERSORT”和“WGCNA”R 包确定高级透明细胞肾细胞癌亚组之间免疫浸润水平的差异。使用 Search Tools for the Retrieval of Interacting Genes 数据库和 Cytoscape 构建蛋白质-蛋白质相互作用网络。包含 CCK-8 和集落形成实验的体外实验。
总共鉴定出 244 个潜在的肿瘤抗原。使用最小绝对收缩和选择算子 Cox 回归，选择 21 个肿瘤抗原用于开发风险评估标志物。风险评分标志物可以作为预测高级透明细胞肾细胞癌患者结局的有用工具。根据差异的临床、分子和免疫相关基因，我们将高级透明细胞肾细胞癌患者分为免疫“冷”亚型和免疫“热”亚型。通过开发逻辑评分，可以更好地区分免疫亚型，更有可能是免疫“冷”亚型或免疫“热”亚型的患者。有趣的是，高风险评分的患者具有更高比例的免疫“热”亚型，而低风险评分的患者则较少。此外，当结合风险评分和免疫亚型时，预后价值得到显著提高。观察到不同肿瘤亚型之间存在不同的免疫景观和信号通路。最后，鉴定出与氧化应激相关的新型肿瘤抗原。
基于肿瘤抗原的风险评分和免疫亚型标志物鉴定了潜在有效的新型抗原，用于开发高级透明细胞肾细胞癌信使 RNA 疫苗，低风险评分和免疫“冷”亚型肿瘤的患者更有可能从信使 RNA 疫苗接种中受益。此外，我们的研究强调了氧化应激在确定信使 RNA 疫苗疗效方面的重要作用。
