Thousands of novel unannotated proteins expand the MHC I immunopeptidome in cancer
Ouspenskaia, T.; Law, T.; Clauser, K. R.; Klaeger, S.; Sarkizova, S.; Aguet, F.; Li, B.; Christian, E.; Knisbacher, B. A.; Le, P. M.; Hartigan, C. R.; Keshishian, H.; Apffel, A.; Oliveira, G.; Zhang, W.; Chow, Y. T.; Ji, Z.; Shukla, S. A.; Bachireddy, P.; Getz, G.; Hacohen, N.; Keskin, D. B.; Carr, S. A.; Wu, C. J.; Regev, A.
Show abstract
Tumor epitopes - peptides that are presented on surface-bound MHC I proteins - provide targets for cancer immunotherapy and have been identified extensively in the annotated protein-coding regions of the genome. Motivated by the recent discovery of translated novel unannotated open reading frames (nuORFs) using ribosome profiling (Ribo-seq), we hypothesized that cancer-associated processes could generate nuORFs that can serve as a new source of tumor antigens that harbor somatic mutations or show tumor-specific expression. To identify cancer-specific nuORFs, we generated Ribo-seq profiles for 29 malignant and healthy samples, developed a sensitive analytic approach for hierarchical ORF prediction, and constructed a high-confidence database of translated nuORFs across tissues. Peptides from 3,555 unique translated nuORFs were presented on MHC I, based on analysis of an extensive dataset of MHC I-bound peptides detected by mass spectrometry, with >20-fold more nuORF peptides detected in the MHC I immunopeptidomes compared to whole proteomes. We further detected somatic mutations in nuORFs of cancer samples and identified nuORFs with tumor-specific translation in melanoma, chronic lymphocytic leukemia and glioblastoma. NuORFs thus expand the pool of MHC I-presented, tumor-specific peptides, targetable by immunotherapies.
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