肿瘤抗原和免疫亚型指导肾透明细胞癌的 mRNA 疫苗开发。

Tumor antigens and immune subtypes guided mRNA vaccine development for kidney renal clear cell carcinoma.

机构信息

Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China.

Department of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China.

出版信息

Mol Cancer. 2021 Dec 6;20(1):159. doi: 10.1186/s12943-021-01465-w.

Abstract

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.

摘要

目前肾透明细胞癌 (KIRC) 的治疗策略有限。肿瘤相关抗原,尤其是基于新抗原的个体化 mRNA 疫苗,代表了实体瘤的新策略,并表现出临床获益,但只有一小部分患者从中受益,这促使我们识别有效的抗原和合适的人群,以促进 mRNA 疫苗在癌症治疗中的应用。通过在 TCGA-KIRC 数据集上进行表达、突变、生存和相关性分析,我们鉴定了四个基因,包括 DNA 拓扑异构酶 II 阿尔法 (TOP2A)、中性粒细胞胞浆因子 4 (NCF4)、formin 样蛋白 1 (FMNL1) 和对接蛋白 3 (DOK3),作为潜在的 KIRC 特异性新抗原候选物。这四个基因在 TCGA-KIRC 中上调、突变,并与生存和抗原呈递细胞呈正相关。此外,我们鉴定了两种免疫亚型,命名为肾细胞癌免疫亚型 1 (RIS1) 和 RIS2。RIS1 和 RIS2 之间存在明显的临床、分子和免疫相关特征。RIS2 患者的生存结局优于 RIS1 患者。进一步的综合免疫相关分析表明,RIS1 是免疫上“热”的,代表一种免疫抑制表型,而 RIS2 代表一种免疫上“冷”的表型。RIS1 和 RIS2 还表现出与肿瘤浸润免疫细胞和免疫检查点相关基因的不同特征。此外,免疫图谱构建确定了每位 KIRC 患者的免疫细胞成分,预测了他们的生存结局,并辅助个体化 mRNA 疫苗的开发。总之,我们的研究鉴定了 TOP2A、NCF4、FMNL1 和 DOK3 作为 KIRC mRNA 疫苗开发的潜在有效新抗原,RIS2 肿瘤患者可能从 mRNA 疫苗接种中获益更多。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a8b7/8647469/6f7872b17d2d/12943_2021_1465_Fig1_HTML.jpg

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