美国圣路易斯华盛顿大学Ting Wang等研究人员合作发现，表观遗传疗法通过增强转座子转录在胶质母细胞瘤细胞中创造肿瘤富集抗原。这一研究成果于2024年9月2日在线发表在国际学术期刊《自然—遗传学》上。

研究人员探讨了表观遗传疗法激活的TE是否可以显著增加胶质母细胞瘤中的抗原库。胶质母细胞瘤是一种侵袭性脑癌，其突变和新抗原负担较低。

研究人员处理了来自患者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，使用表观遗传药物识别出在癌细胞中优先表达的、由治疗引发的转座元件（TE）来源转录物。通过液相色谱-串联质谱（LC-MS/MS）结合实验，研究人员验证了这些转录物能够产生人类白细胞抗原（HLA）I类呈递的抗原。

重要的是，即使在表观遗传治疗后的增殖非肿瘤细胞系中，许多TE也被转录，这表明类似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。这些结果强调了在利用治疗诱导的TE衍生抗原进行靶向免疫治疗时既需谨慎又具有前景。

研究人员表示，通过抑制表观遗传调节因子可以转录性地重新激活TE。这些TE转录物通常会生成独特的肽，可以作为免疫治疗的免疫原抗原。

附：英文原文

Title: Epigenetic therapy potentiates transposable element transcription to create tumor-enriched antigens in glioblastoma cells

Author: Jang, H. Josh, Shah, Nakul M., Maeng, Ju Heon, Liang, Yonghao, Basri, Noah L., Ge, Jiaxin, Qu, Xuan, Mahlokozera, Tatenda, Tzeng, Shin-Cheng, Williams, Russell B., Moore, Michael J., Annamalai, Devi, Chen, Justin Y., Lee, Hyung Joo, DeSouza, Patrick A., Li, Daofeng, Xing, Xiaoyun, Kim, Albert H., Wang, Ting

Issue&Volume: 2024-09-02

Abstract: 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. Treatment of primary glioblastoma cell lines with epigenetic therapy reactivates transposable elements (TEs). TE-derived transcripts can produce human leukocyte antigen class I-presented antigens, which could potentially be therapeutically targeted.

DOI: 10.1038/s41588-024-01880-x

Source: https://www.nature.com/articles/s41588-024-01880-x