Identification of cryptic neoepitopes generated by chimeric transcripts in ovarian cancer

Abstract

Peptides identified in a customized targeted database were assessed for antigenicity. Further docking of peptide – MHC as well as peptide-MHC-TCR complexes provided proof-of-concept of antigenicity. Considerable recent interest lies in the immunogenicity of non-canonical neoantigens generated by alternative ORFs emerging from non-synonymous mutations or nucleotide insertions and deletions, exonization of untranslated regions of the genome, non-coding transcripts, transposable elements, etc. Amongst these ‘cryptic’ epitopes, those derived from chimeric transcripts which harbor sequences derived from more than one gene remain undefined, since the translational potential and immunogenicity of these transcripts is relatively unexplored. The present study was hence designed to predict and assess the neoepitopes generated by chimeric transcripts in ovarian cancer. Using a customized targeted database, we identified peptides uniquely generated by such transcripts, expressed either as reading-frame or sense/anti-sense isoforms. Further assessment of the antigenicity of these peptides identified a small number of putative neoepitopes that are likely to be presented to MHC-I in an allele-specific manner, and further recognized by specific TCRs. Effectively, such generation of chimeric molecules by relaxed rigidity of canonical transcription and translation may present opportunities in immunotherapy.