Although most characterized tumor antigens are encoded by canonical transcripts (such as differentiation or tumor-testis antigens) or mutations (both driver and passenger mutations), recent results have shown that noncanonical transcripts including long noncoding RNAs and transposable elements (TEs) can also encode tumor-specific neo-antigens. Here, we investigate the presentation and immunogenicity of tumor antigens derived from noncanonical mRNA splicing events between coding exons and TEs. Comparing human non–small cell lung cancer (NSCLC) and diverse healthy tissues, we identified a subset of splicing junctions that is both tumor specific and shared across patients. We used HLA-I peptidomics to identify peptides encoded by tumor-specific junctions in primary NSCLC samples and lung tumor cell lines. Recurrent junction-encoded peptides were immunogenic in vitro, and CD8 + T cells specific for junction-encoded epitopes were present in tumors and tumor-draining lymph nodes from patients with NSCLC. We conclude that noncanonical splicing junctions between exons and TEs represent a source of recurrent, immunogenic tumor-specific antigens in patients with NSCLC.

中文翻译：

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外显子和转座元件之间的非经典剪接点是肺癌患者免疫原性复发性新抗原的来源

尽管大多数特征性肿瘤抗原由规范转录本（如分化或肿瘤-睾丸抗原）或突变（驱动突变和乘客突变）编码，但最近的结果表明，包括长链非编码 RNA 和转座因子 (TE) 在内的非规范转录本也可以编码肿瘤特异性新抗原。在这里，我们研究了源自编码外显子和 TE 之间的非规范 mRNA 剪接事件的肿瘤抗原的呈现和免疫原性。比较人类非小细胞肺癌 (NSCLC) 和不同的健康组织，我们确定了一个剪接点子集，该子集既具有肿瘤特异性，又在患者之间共享。我们使用 HLA-I 肽组学来鉴定由原代 NSCLC 样本和肺肿瘤细胞系中的肿瘤特异性连接编码的肽。+NSCLC 患者的肿瘤和肿瘤引流淋巴结中存在对连接编码表位具有特异性的 T 细胞。我们得出结论，外显子和 TE 之间的非典型剪接点代表了 NSCLC 患者中复发性免疫原性肿瘤特异性抗原的来源。