Splicing neoantigen discovery with SNAF reveals shared targets for cancer immunotherapy.

Autor: Li G; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Department of Biomedical Informatics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA., Mahajan S; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Ma S; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Jeffery ED; Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22903, USA., Zhang X; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Bhattacharjee A; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Venkatasubramanian M; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Department of Computer Science, University of Cincinnati, Cincinnati, OH 45229, USA., Weirauch MT; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.; Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA., Miraldi ER; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA., Grimes HL; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA., Sheynkman GM; Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22903, USA., Tilburgs T; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA., Salomonis N; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Department of Biomedical Informatics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2024 Jan 17; Vol. 16 (730), pp. eade2886. Date of Electronic Publication: 2024 Jan 17.
DOI: 10.1126/scitranslmed.ade2886
Abstrakt: 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.
Databáze: MEDLINE
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