DataSheet_8_Systematically Characterizing A-to-I RNA Editing Neoantigens in Cancer.xlsx

A-to-I RNA editing can contribute to the transcriptomic and proteomic diversity of many diseases including cancer. It has been reported that peptides generated from RNA editing could be naturally presented by human leukocyte antigen (HLA) molecules and elicit CD8+ T cell activation. However, a systematical characterization of A-to-I RNA editing neoantigens in cancer is still lacking. Here, an integrated RNA-editing based neoantigen identification pipeline PREP (Prioritizing of RNA Editing-based Peptides) was presented. A comprehensive RNA editing neoantigen profile analysis on 12 cancer types from The Cancer Genome Atlas (TCGA) cohorts was performed. PREP was also applied to 14 ovarian tumor samples and two clinical melanoma cohorts treated with immunotherapy. We finally proposed an RNA editing neoantigen immunogenicity score scheme, i.e. REscore, which takes RNA editing level and infiltrating immune cell population into consideration. We reported variant peptide from protein IFI30 in breast cancer which was confirmed expressed and presented in two samples with mass spectrometry data support. We showed that RNA editing neoantigen could be identified from RNA-seq data and could be validated with mass spectrometry data in ovarian tumor samples. Furthermore, we characterized the RNA editing neoantigen profile of clinical melanoma cohorts treated with immunotherapy. Finally, REscore showed significant associations with improved overall survival in melanoma cohorts treated with immunotherapy. These findings provided novel insights of cancer biomarker and enhance our understanding of neoantigen derived from A-to-I RNA editing as well as more types of candidates for personalized cancer vaccines design in the context of cancer immunotherapy.

A-to-I RNA编辑（A-to-I RNA editing）可促进包括癌症在内的诸多疾病的转录组与蛋白质组多样性。已有研究显示，由RNA编辑产生的肽段可自然呈递于人类白细胞抗原（human leukocyte antigen, HLA）分子，并能激活CD8+ T细胞。然而，目前仍缺乏对癌症中A-to-I RNA编辑新抗原的系统性表征。本研究构建了一款基于RNA编辑的新抗原识别整合流程PREP（Prioritizing of RNA Editing-based Peptides，即RNA编辑肽段优先排序工具）。我们对来自癌症基因组图谱（The Cancer Genome Atlas, TCGA）队列的12种癌症类型开展了全面的RNA编辑新抗原特征分析。同时，将PREP应用于14例卵巢肿瘤样本以及2个接受免疫治疗的临床黑色素瘤队列。本研究最终提出了一款RNA编辑新抗原免疫原性评分方案REscore，该方案综合考量了RNA编辑水平与肿瘤浸润免疫细胞群体特征。我们在乳腺癌中发现了源自IFI30蛋白的变异肽段，该肽段的表达与呈递情况在2例样本中得到了质谱数据的验证。研究证实，可通过RNA测序（RNA-seq）数据识别RNA编辑新抗原，并可在卵巢肿瘤样本中通过质谱数据完成验证。此外，我们还对接受免疫治疗的临床黑色素瘤队列的RNA编辑新抗原特征进行了系统性表征。最后，REscore评分与接受免疫治疗的黑色素瘤队列患者的总生存期改善呈显著相关性。本研究发现为癌症生物标志物研究提供了全新视角，加深了我们对A-to-I RNA编辑衍生新抗原的认知，同时为癌症免疫治疗背景下的个性化癌症疫苗设计提供了更多候选靶点。