Unconventional tumor antigens take off
Most identified tumor-specific antigens are derived from coding regions of the genome that are mutated or overexpressed in tumors, but non-coding regions can also generate MHC-I–presented peptides. Two studies in this issue demonstrate that mRNA splicing events between exons and transposable elements (TEs) can encode immunogenic peptides eliciting T cell responses in human and murine tumors. Merlotti et al. showed that expression of certain exon-TE splicing junctions is tumor-specific in humans and that T cells specific for encoded HLA-I peptides are found in NSCLC patients. In mouse models, Burbage et al. found that immunization with peptides derived from these transcripts slowed tumor growth and that the histone methyltransferase Setdb1 repressed expression of several immunogenic exon-TE splicing junctions. Together, these studies identify exon-TE splicing junctions as a class of immunogenic tumor neo-antigens. See related Research Article by Merlotti et al.—CO
Abstract
Oncogenesis often implicates epigenetic alterations, including derepression of transposable elements (TEs) and defects in alternative splicing. Here, we explore the possibility that noncanonical splice junctions between exons and TEs represent a source of tumor-specific antigens. We show that mouse normal tissues and tumor cell lines express wide but distinct ranges of mRNA junctions between exons and TEs, some of which are tumor specific. Immunopeptidome analyses in tumor cell lines identified peptides derived from exon-TE splicing junctions associated to MHC-I molecules. Exon-TE junction–derived peptides were immunogenic in tumor-bearing mice. Both prophylactic and therapeutic vaccinations with junction-derived peptides delayed tumor growth in vivo. Inactivation of the TE-silencing histone 3–lysine 9 methyltransferase Setdb1 caused overexpression of new immunogenic junctions in tumor cells. Our results identify exon-TE splicing junctions as epigenetically controlled, immunogenic, and protective tumor antigens in mice, opening possibilities for tumor targeting and vaccination in patients with cancer.