Martin et al. utilized whole-genome sequencing and long- and short-read RNAseq to comprehensively identify neo-open reading frame peptides (NOPs) forming the “framome” (comprising over 2,000 aa for some of 61 analyzed tumors). Neo-ORFs were formed by stop loss and splice mutations (2%), indels (12%), structural genomic variants (SV) leading to fusion proteins (37%) or, especially, the expression of a usually non-coding region of the genome (49%; “hidden NOPs”). Peptides derived from NOPs could be detected by immunopeptidomics, and hidden NOP-specific CD8+ effector memory T cells were detected in a patient sample.
Contributed by Ute Burkhardt
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.
Author Info: (1) CureVac Netherlands B.V., Amsterdam, Netherlands. (2) CureVac Netherlands B.V., Amsterdam, Netherlands. (3) CureVac Netherlands B.V., Amsterdam, Netherlands. (4) CureVac Nether
Author Info: (1) CureVac Netherlands B.V., Amsterdam, Netherlands. (2) CureVac Netherlands B.V., Amsterdam, Netherlands. (3) CureVac Netherlands B.V., Amsterdam, Netherlands. (4) CureVac Netherlands B.V., Amsterdam, Netherlands. (5) CureVac Netherlands B.V., Amsterdam, Netherlands. (6) CureVac Netherlands B.V., Amsterdam, Netherlands. (7) Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands. (8) Amsterdam UMC, Netherlands. (9) Amsterdam UMC, University of Amsterdam, Amsterdam, NH, Netherlands. (10) University of Groningen and University Medical Center Groningen, Groningen, Netherlands. (11) Duke University, Durham, NC, United States. (12) Duke University, Durham, NC, United States. (13) Duke Medical Center, Durham, NC, United States. (14) University of Southampton, Liverpool, Merseyside, United Kingdom. (15) University Hospitals Dorset, Poole, United Kingdom. (16) Amsterdam UMC, Amsterdam, Netherlands. (17) Amsterdam UMC, location AMC, Amsterdam, Netherlands. (18) Erasmus MC, Rotterdam, Netherlands. (19) The Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands. (20) The Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands. (21) Princess Máxima Center for Pediatric Oncology, Utrecht, Utrecht, Netherlands. (22) Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands. (23) Sanquin Reagents, Sanquin, Amsterdam, Netherlands. (24) CureVac Netherlands B.V., Amsterdam, Netherlands. (25) Academic Medical Center, Amsterdam, Netherlands. (26) Netherlands Cancer Institute, Amsterdam, Netherlands. (27) Erasmus MC, Rotterdam, Netherlands. (28) Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands. (29) University of Groningen, University Medical Center Groningen, Groningen, Netherlands. (30) University Medical Center Groningen, Groningen, I am not in the U.S. or Canada, Netherlands. (31) University of Groningen, Groningen, Netherlands. (32) Erasmus MC Cancer Institute, Rotterdam, Netherlands. (33) Princess Máxima Center, Utrecht, Utrecht, Netherlands. (34) Erasmus Medical Centre Rotterdam. (35) CureVac Netherlands B.V., Amsterdam, Netherlands. (36) CureVac Netherlands B.V., Amsterdam, Netherlands.
