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, Renée 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 A G 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 L T van Kempen, Harry J M Groen, Joachim G J V Aerts, Sebastiaan van Heesch, Bob Löwenberg, Ronald Plasterk, Wigard P Kloosterman

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

Identification of immunogenic cancer neoantigens as targets for therapy is challenging. Here, we integrate the whole-genome and long-read transcript sequencing of cancers to identify the collection of neo-open reading frame peptides (NOP) expressed in tumors. We termed this collection of NOPs the tumor framome. NOPs represent tumor-specific peptides that are different from wild-type proteins and may be strongly immunogenic. We describe a class of hidden NOPs that derive from structural genomic variants involving an upstream protein coding gene driving expression and translation of noncoding regions of the genome downstream of a rearrangement breakpoint, i.e., where no gene annotation or evidence for transcription exists. The entire collection of NOPs represents a vast number of possible neoantigens particularly in tumors with many 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 peripheral blood from a patient with lung cancer. This work highlights NOPs as a major source of possible neoantigens for personalized cancer immunotherapy and provides a rationale for analyzing the complete cancer genome and transcriptome as a basis for the detection of NOPs.

Originele taal-2Engels
Pagina's (van-tot)759-778
Aantal pagina's20
TijdschriftCancer immunology research
Volume12
Nummer van het tijdschrift6
DOI's
StatusGepubliceerd - 4 jun. 2024
Extern gepubliceerdJa

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