Abstract
A-to-I RNA editing can contribute to the transcriptomic and proteomic diversity of many diseases including cancer. It has been reported that peptides generated from RNA editing could be naturally presented by human leukocyte antigen (HLA) molecules and elicit CD8+ T cell activation. However, a systematical characterization of A-to-I RNA editing neoantigens in cancer is still lacking. Here, an integrated RNA-editing based neoantigen identification pipeline PREP (Prioritizing of RNA Editing-based Peptides) was presented. A comprehensive RNA editing neoantigen profile analysis on 12 cancer types from The Cancer Genome Atlas (TCGA) cohorts was performed. PREP was also applied to 14 ovarian tumor samples and two clinical melanoma cohorts treated with immunotherapy. We finally proposed an RNA editing neoantigen immunogenicity score scheme, i.e. REscore, which takes RNA editing level and infiltrating immune cell population into consideration. We reported variant peptide from protein IFI30 in breast cancer which was confirmed expressed and presented in two samples with mass spectrometry data support. We showed that RNA editing neoantigen could be identified from RNA-seq data and could be validated with mass spectrometry data in ovarian tumor samples. Furthermore, we characterized the RNA editing neoantigen profile of clinical melanoma cohorts treated with immunotherapy. Finally, REscore showed significant associations with improved overall survival in melanoma cohorts treated with immunotherapy. These findings provided novel insights of cancer biomarker and enhance our understanding of neoantigen derived from A-to-I RNA editing as well as more types of candidates for personalized cancer vaccines design in the context of cancer immunotherapy.
Highlights
Cancer immunotherapy strategies including adoptive T-cell transfer (ACT) with Chimeric antigen receptor T-cell (CAR-T) or Tumor Infiltrating T-cell (TIL), cancer vaccine and immune checkpoint blockade with anti-CTLA4/anti-PD1 inhibitors have exhibited tremendous clinical power in cancer treatment [1,2,3]
We identified a median of 68 candidate neoantigen per sample in breast cancer (Table S4), which has a significantly higher RNA editing (RE) neoantigen burden compared to those of other cancer types (Figure 2A) (Wilcoxon rank sum test p < 0.05 for all, Table S5A)
We found that breast cancer has a significantly higher RE neoantigen burden than somatic neoantigen burden compared to other cancer types (Figure 2B), indicating that RE neoantigen might play a pivotal role in this specific cancer type
Summary
Cancer immunotherapy strategies including adoptive T-cell transfer (ACT) with Chimeric antigen receptor T-cell (CAR-T) or Tumor Infiltrating T-cell (TIL), cancer vaccine and immune checkpoint blockade with anti-CTLA4/anti-PD1 inhibitors have exhibited tremendous clinical power in cancer treatment [1,2,3]. The A-to-I [detected as adenosine-to-guanosine (A to G) mismatches in transcriptome] RE (hereinafter referred to as RE) is the most common type of RE in human It is catalyzed by the adenosine deaminases that act on RNA (ADARs) family of enzymes, which bind double-stranded RNA (dsRNA) and transform adenosines into inosines at specific positions. It has been reported that elevated RE may facilitate the specific autoimmune disease, i.e., Systemic Lupus
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