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Splicing neoantigen discovery with SNAF reveals shared targets for cancer immunotherapy

RNA剪接 生物 选择性拼接 免疫疗法 计算生物学 表位 抗原 免疫原性 癌症免疫疗法 癌症研究 免疫系统 核糖核酸 免疫学 遗传学 基因 外显子
作者
Guangyuan Li,Shweta Mahajan,Siyuan Ma,Erin D. Jeffery,Xuan Zhang,Anukana Bhattacharjee,Meenakshi Venkatasubramanian,Matthew T. Weirauch,Emily R. Miraldi,H. Leighton Grimes,Gloria Sheynkman,Tamara Tilburgs,Nathan Salomonis
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science (AAAS)]
卷期号:16 (730) 被引量:16
标识
DOI:10.1126/scitranslmed.ade2886
摘要

Immunotherapy has emerged as a crucial strategy to combat cancer by “reprogramming” a patient’s own immune system. Although immunotherapy is typically reserved for patients with a high mutational burden, neoantigens produced from posttranscriptional regulation may provide an untapped reservoir of common immunogenic targets for new targeted therapies. To comprehensively define tumor-specific and likely immunogenic neoantigens from patient RNA-Seq, we developed Splicing Neo Antigen Finder (SNAF), an easy-to-use and open-source computational workflow to predict splicing-derived immunogenic MHC-bound peptides (T cell antigen) and unannotated transmembrane proteins with altered extracellular epitopes (B cell antigen). This workflow uses a highly accurate deep learning strategy for immunogenicity prediction (DeepImmuno) in conjunction with new algorithms to rank the tumor specificity of neoantigens (BayesTS) and to predict regulators of mis-splicing (RNA-SPRINT). T cell antigens from SNAF were frequently evidenced as HLA-presented peptides from mass spectrometry (MS) and predict response to immunotherapy in melanoma. Splicing neoantigen burden was attributed to coordinated splicing factor dysregulation. Shared splicing neoantigens were found in up to 90% of patients with melanoma, correlated to overall survival in multiple cancer cohorts, induced T cell reactivity, and were characterized by distinct cells of origin and amino acid preferences. In addition to T cell neoantigens, our B cell focused pipeline (SNAF-B) identified a new class of tumor-specific extracellular neoepitopes, which we termed ExNeoEpitopes. ExNeoEpitope full-length mRNA predictions were tumor specific and were validated using long-read isoform sequencing and in vitro transmembrane localization assays. Therefore, our systematic identification of splicing neoantigens revealed potential shared targets for therapy in heterogeneous cancers.
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