The neo-open reading frame peptides that comprise the tumor framome are a rich source of neoantigens for cancer immunotherapy

Michael V Martin, Salvador Aguilar-Rosas, Katka Franke, Mark Pieterse, Jamie van Langelaar, Renee RCE Schreurs, Maarten F Bijlsma, Marc G Besselink, Jan Koster, Wim Timens, Mustafa Khasraw, David M Ashley, Stephen T Keir, Christian H Ottensmeier, Emma V King, Joanne Verheij, Cynthia Waasdorp, Peter J M Valk, Sem AG Engels, Ellen OostenbachJip T van Dinter, Damon A Hofman, Juk Yee Mok, Wim J E van Esch, Hanneke Wilmink, Kim Monkhorst, Henk M W Verheul, Dennis Poel, T Jeroen N Hiltermann, Léon C van Kempen, Harry Jm Groen, Joachim G J V Aerts, Sebastiaan van Heesch, Bob Lowenberg, Ronald Plasterk, Wigard P Kloosterman*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Identification of immunogenic cancer neoantigens as targets for therapy is challenging. Here, we integrate cancer whole genome and long-read transcript sequencing to identify the collection of novel open reading frame peptides (NOPs) expressed in tumors, termed the framome. NOPs represent tumor-specific peptides that are different from wild-type proteins and may be strongly immunogenic. We describe an uncharacterized class of hidden NOPs, which derive from structural genomic variants involving an upstream protein coding gene driving expression and translation of non-coding regions of the genome downstream of a rearrangement breakpoint. NOPs represent a vast amount of possible neoantigens particularly in tumors with many (complex) structural genomic variants and a low number of missense mutations. We show that NOPs are immunogenic and epitopes derived from NOPs can bind to MHC class I molecules. Finally, we provide evidence for the presence of memory T-cells specific for hidden NOPs in lung cancer patient peripheral blood.

Original languageEnglish
Number of pages41
JournalCancer immunology research
DOIs
Publication statusE-pub ahead of print - 4-Apr-2024

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