Current treatment strategy for kidney renal clear cell carcinoma (KIRC) is limited. Tumor-associated antigens, especially neoantigen-based personalized mRNA vaccines represent new strategies and manifest clinical benefits in solid tumors, but only a small proportion of patients could benefit from them, which prompts us to identify effective antigens and suitable populations to facilitate mRNA vaccines application in cancer therapy. Through performing expression, mutation, survival and correlation analyses in TCGA-KIRC dataset, we identified four genes including DNA topoisomerase II alpha (TOP2A), neutrophil cytosol factor 4 (NCF4), formin-like protein 1 (FMNL1) and docking protein 3 (DOK3) as potential KIRC-specific neoantigen candidates. These four genes were upregulated, mutated and positively associated with survival and antigen-presenting cells in TCGA-KIRC. Furthermore, we identified two immune subtypes, named renal cell carcinoma immune subtype 1 (RIS1) and RIS2, of KIRC. Distinct clinical, molecular and immune-related signatures were observed between RIS1 and RIS2. Patients of RIS2 had better survival outcomes than those of RIS1. Further comprehensive immune-related analyses indicated that RIS1 is immunologically “hot” and represent an immunosuppressive phenotype, whereas RIS2 represents an immunologically “cold” phenotype. RIS1 and RIS2 also showed differential features with regard to tumor infiltrating immune cells and immune checkpoint-related genes. Moreover, the immune landscape construction identified the immune cell components of each KIRC patient, predicted their survival outcomes, and assisted the development of personalized mRNA vaccines. In summary, our study identified TOP2A, NCF4, FMNL1 and DOK3 as potential effective neoantigens for KIRC mRNA vaccine development, and patients with RIS2 tumor might benefit more from mRNA vaccination.

中文翻译：

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肿瘤抗原和免疫亚型指导肾透明细胞癌的 mRNA 疫苗开发

目前肾透明细胞癌（KIRC）的治疗策略是有限的。肿瘤相关抗原，尤其是基于新抗原的个性化 mRNA 疫苗代表了新策略并在实体瘤中表现出临床益处，但只有一小部分患者可以从中受益，这促使我们确定有效的抗原和合适的人群以促进 mRNA 疫苗的应用在癌症治疗中。通过在 TCGA-KIRC 数据集中进行表达、突变、存活和相关性分析，我们确定了四个基因，包括 DNA 拓扑异构酶 II α (TOP2A)、中性粒细胞溶质因子 4 (NCF4)、formin 样蛋白 1 (FMNL1) 和对接蛋白 3。 DOK3) 作为潜在的 KIRC 特异性新抗原候选者。这四个基因被上调，突变并与 TCGA-KIRC 中的存活和抗原呈递细胞呈正相关。此外，我们确定了 KIRC 的两种免疫亚型，称为肾细胞癌免疫亚型 1 (RIS1) 和 RIS2。在 RIS1 和 RIS2 之间观察到不同的临床、分子和免疫相关特征。RIS2 患者的生存结果优于 RIS1 患者。进一步全面的免疫相关分析表明，RIS1 在免疫学上是“热”的，代表一种免疫抑制表型，而 RIS2 在免疫学上是“冷”表型。RIS1 和 RIS2 在肿瘤浸润免疫细胞和免疫检查点相关基因方面也表现出不同的特征。此外，免疫景观构建确定了每个 KIRC 患者的免疫细胞成分，预测了他们的生存结果，并协助开发个性化mRNA疫苗。总之，我们的研究将 TOP2A、NCF4、FMNL1 和 DOK3 确定为 KIRC mRNA 疫苗开发的潜在有效新抗原，RIS2 肿瘤患者可能从 mRNA 疫苗中获益更多。