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 Köster, 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 Oostenbach, Jip 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 H.A. Plasterk, Wigard P. Kloosterman
Abstract
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.