Table_2_Circular RNAs as a potential source of neoepitopes in cancer.xlsx

Neoepitopes have attracted much attention as targets for immunotherapy against cancer. Therefore, efficient neoepitope screening technology is an essential step in the development of personalized vaccines. Circular RNAs (circRNAs) are generated by back-splicing and have a single-stranded continuous circular structure. So far, various circRNAs have been poorly characterized, though new evidence suggests that a few translated circRNAs may play a role in cancer. In the present study, circRNA was used as a source of neoepitope, a novel strategy as circRNA-derived neoepitopes have never been previously explored. The present study reports CIRC_neo (circRNA-derived neoepitope prediction pipeline), which is a comprehensive and automated bioinformatic pipeline for the prediction of circRNA-derived neoepitopes from RNA sequencing data. The computational prediction from sequencing data requires complex computational workflows to identify circRNAs, derive the resulting peptides, infer the types of human leukocyte antigens (HLA I and HLA II) in patients, and predict the neoepitopes binding to these antigens. The present study proposes a novel source of neoepitopes. The study focused on cancer-specific circRNAs, which have greatly expanded the source pool for neoepitope discovery. The statistical analysis of different features of circRNA-derived neoepitopes revealed that circRNAs could produce long proteins or truncated proteins. Because the peptides were completely foreign to the human body, they could be highly immunogenic. Importantly, circRNA-derived neoepitopes capable of binding to HLA were discovered. In the current study, circRNAs were systematically analyzed, revealing potential targets and novel research clues for cancer diagnosis, treatment, and prospective personalized vaccine research.

新表位（neoepitopes）作为癌症免疫治疗的靶点受到广泛关注。因此，高效的新表位筛选技术是个性化疫苗研发过程中的关键环节。环状RNA（circRNAs）通过反向剪接生成，具有单链连续环状结构。迄今为止，多数环状RNA的功能特征尚未得到充分解析，尽管最新研究证据表明，少数可翻译的环状RNA可能参与癌症发生发展进程。本研究将环状RNA作为新表位的来源，这是一种全新的研究策略——此前从未有研究探索过环状RNA衍生新表位。本研究报道了CIRC_neo（环状RNA衍生新表位预测流程），这是一款可从RNA测序数据中预测环状RNA衍生新表位的全面且自动化的生物信息学流程。从测序数据开展计算预测需依托复杂的计算工作流，依次完成环状RNA识别、对应肽段推导、患者人类白细胞抗原（human leukocyte antigens，简称HLA）I型与II型分型，以及新表位与对应抗原结合亲和力预测等步骤。本研究提出了一种全新的新表位来源方向，研究聚焦于癌症特异性环状RNA，这极大拓宽了新表位发现的资源库。对环状RNA衍生新表位的多维度特征进行统计分析后发现，环状RNA可编码全长蛋白质或截短蛋白质。由于此类肽段完全外源性，因此具备极高的免疫原性。尤为重要的是，本研究成功筛选出可与HLA分子结合的环状RNA衍生新表位。本研究通过对环状RNA的系统性分析，为癌症诊断、治疗以及未来个性化疫苗研发提供了潜在靶点与全新研究思路。