抑制表观遗传调节剂可以转录重新激活转座元件（TE）。这些 TE 转录物通常会产生独特的肽，可以作为免疫治疗的免疫原性抗原。在这里，我们询问表观遗传疗法激活的 TE 是否可以明显增加胶质母细胞瘤（一种具有低突变和新抗原负担的侵袭性脑癌）的抗原库。我们用表观遗传药物治疗患者来源的原代胶质母细胞瘤干细胞系、星形胶质细胞系和原代成纤维细胞系，并鉴定了治疗诱导的 TE 衍生转录物，这些转录物优先在癌细胞中表达。我们使用液相色谱和串联质谱下拉实验验证了这些转录物可以产生人类白细胞抗原 I 类呈递的抗原。重要的是，在表观遗传治疗后，许多 TE 也被转录，即使是在增殖的非肿瘤细胞系中，这表明 CRISPR 介导的激活等靶向策略可以最大限度地减少激活不需要的基因组区域的潜在副作用。结果强调了谨慎的必要性和未来利用治疗诱导的 TE 衍生抗原进行靶向免疫治疗的转化努力的希望。© 2024。作者获得 Springer Nature America, Inc. 的独家许可。

Inhibiting epigenetic modulators can transcriptionally reactivate transposable elements (TEs). These TE transcripts often generate unique peptides that can serve as immunogenic antigens for immunotherapy. Here, we ask whether TEs activated by epigenetic therapy could appreciably increase the antigen repertoire in glioblastoma, an aggressive brain cancer with low mutation and neoantigen burden. We treated patient-derived primary glioblastoma stem cell lines, an astrocyte cell line and primary fibroblast cell lines with epigenetic drugs, and identified treatment-induced, TE-derived transcripts that are preferentially expressed in cancer cells. We verified that these transcripts could produce human leukocyte antigen class I-presented antigens using liquid chromatography with tandem mass spectrometry pulldown experiments. Importantly, many TEs were also transcribed, even in proliferating nontumor cell lines, after epigenetic therapy, which suggests that targeted strategies like CRISPR-mediated activation could minimize potential side effects of activating unwanted genomic regions. The results highlight both the need for caution and the promise of future translational efforts in harnessing treatment-induced TE-derived antigens for targeted immunotherapy.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.