Oncogenesis often implicates epigenetic alterations, including derepression of transposable elements (TEs) and defects in alternative splicing. Here, we explore the possibility that noncanonical splice junctions between exons and TEs represent a source of tumor-specific antigens. We show that mouse normal tissues and tumor cell lines express wide but distinct ranges of mRNA junctions between exons and TEs, some of which are tumor specific. Immunopeptidome analyses in tumor cell lines identified peptides derived from exon-TE splicing junctions associated to MHC-I molecules. Exon-TE junction–derived peptides were immunogenic in tumor-bearing mice. Both prophylactic and therapeutic vaccinations with junction-derived peptides delayed tumor growth in vivo. Inactivation of the TE-silencing histone 3–lysine 9 methyltransferase Setdb1 caused overexpression of new immunogenic junctions in tumor cells. Our results identify exon-TE splicing junctions as epigenetically controlled, immunogenic, and protective tumor antigens in mice, opening possibilities for tumor targeting and vaccination in patients with cancer.

中文翻译：

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来自外显子和转座元件之间剪接点的表观遗传控制的肿瘤抗原

肿瘤发生通常涉及表观遗传改变，包括转座元件（TE）的去抑制和选择性剪接的缺陷。在这里，我们探讨了外显子和 TE 之间的非规范剪接点代表肿瘤特异性抗原来源的可能性。我们发现，小鼠正常组织和肿瘤细胞系在外显子和 TE 之间表达广泛但不同范围的 mRNA 连接，其中一些是肿瘤特异性的。肿瘤细胞系中的免疫肽组分析鉴定出源自与 MHC-I 分子相关的外显子 TE 剪接点的肽。外显子-TE 连接衍生的肽在荷瘤小鼠中具有免疫原性。使用连接衍生肽进行预防性和治疗性疫苗接种均可延迟体内肿瘤生长。TE 沉默组蛋白 3-赖氨酸 9 甲基转移酶失活设置db1引起肿瘤细胞中新的免疫原性连接的过度表达。我们的结果确定外显子-TE剪接点是小鼠中表观遗传控制的、免疫原性的和保护性肿瘤抗原，为癌症患者的肿瘤靶向和疫苗接种开辟了可能性。