Pan-cancer tumor-specific antigens and membrane targets from transposable elements

We charted the transcription start sites (TSSs) landscape globally to determine the expressed isoform of each gene and validate the precence of transposable element-derived transcript. Cryptic promoters within transposable elements (TEs) are transcriptionally reactivated in tumors to create novel TE-gene chimeric transcripts, which can produce immunogenic antigens. We performed the most comprehensive screen to date for these TE exaptation events in 33 TCGA tumortypes,675 cancer cell lines, and 11,686 GTEx adult tissue transcriptomes and identified 201,068 TE-exapted candidates with the potential to generate shared tumor-specific TE-chimeric antigens (TS-TEAs). Resultant whole lysate and HLA-pull down mass spectrometry data confirmed that TS-TEAs are presented on cancer cell surfaces. In addition, we highlight the tumor-specific membrane proteins transcribed from TE promoters that can expose novel epitopes on the extracellular surface of cancer cells. Here, we showcase the high pan-cancer prevalence of TS-TEAs and atypical membrane proteins that can be therapeutically exploited through immunotherapy approaches. nanoCAGE libraries was generated for variuos cancer cell lines across different cancer types.

本研究全局绘制了转录起始位点（Transcription Start Sites, TSSs）的调控图谱，以确定每个基因的表达异构体，并验证转座因子来源转录本的存在。转座因子（Transposable Elements, TEs）内部的隐蔽启动子可在肿瘤中被转录激活，进而生成全新的TE-基因嵌合转录本，此类转录本可编码具有免疫原性的抗原。本研究针对33种癌症基因组图谱（The Cancer Genome Atlas, TCGA）肿瘤类型、675株癌细胞系以及11686个基因型-组织表达（Genotype-Tissue Expression, GTEx）成人组织转录组中的此类转座因子外显化（TE exaptation）事件，开展了迄今为止最为全面的筛选，最终鉴定出201068个具备产生共享型肿瘤特异性TE嵌合抗原（Tumor-Specific TE-Chimeric Antigens, TS-TEAs）潜力的转座因子外显化候选事件。后续获取的全细胞裂解液及人类白细胞抗原（Human Leukocyte Antigen, HLA）Pull-down质谱数据证实，TS-TEAs可被呈递于癌细胞表面。此外，本研究还重点解析了由TE启动子转录而来的肿瘤特异性膜蛋白，此类蛋白可在癌细胞的细胞外表面暴露全新的表位。本研究证实了TS-TEAs与非典型膜蛋白在泛癌中的高流行特征，这类分子可通过免疫治疗策略实现临床靶向开发。本研究为不同癌症类型的多种癌细胞系构建了nanoCAGE文库。