Epigenetically controlled tumor antigens derived from splice junctions between exons and transposable elements.

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.

• Authors: Marianne Burbage, Ares Rocañín-Arjó, Blandine Baudon, Yago A Arribas, Antonela Merlotti, Derek C Rookhuizen, Sandrine Heurtebise-Chrétien, Mengliang Ye, Alexandre Houy, Nina Burgdorf, Guadalupe Suarez, Marine Gros, Benjamin Sadacca, Montserrat Carrascal, Andrea Garmilla, Mylène Bohec, Sylvain Baulande, Bérangère Lombard, Damarys Loew, Joshua J Waterfall, Marc-Henri Stern, Christel Goudot, Sebastian Amigorena
• Journal: Science immunology (Sci Immunol) Vol. 8 Issue 80 Pg. eabm6360 (02 03 2023) ISSN: 2470-9468 [Electronic] United States
• PMID: 36735776 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Transposable Elements
• Antigens, Neoplasm
• RNA, Messenger

Topics

• Animals
• Mice
• DNA Transposable Elements (genetics)
• Antigens, Neoplasm (genetics)
• Exons (genetics)
• RNA, Messenger
• Cell Line, Tumor