Questioning whether peptides derived from novel/unannotated open reading frames (nuORFs) may serve as cancer antigens, Ouspenskaia, Law, Clauser, and Klaeger et al. performed ribosome profiling (Ribo-seq) of cancer and healthy samples to compose a nuORF database. NuORFs constituted a significant portion of the MHC-I immunopeptidome (>6500, ~3% of all peptides), were overrepresented relative to nuORFs in the whole proteome, and many were shared between HLA-matched samples. Mutated nuORFs (i.e. potential neoantigens) and nuORFs with enriched translation in cancer were identified in melanoma, CLL, and glioblastoma.
Contributed by Alex Najibi
ABSTRACT: Tumor-associated epitopes presented on MHC-I that can activate the immune system against cancer cells are typically identified from annotated protein-coding regions of the genome, but whether peptides originating from novel or unannotated open reading frames (nuORFs) can contribute to antitumor immune responses remains unclear. Here we show that peptides originating from nuORFs detected by ribosome profiling of malignant and healthy samples can be displayed on MHC-I of cancer cells, acting as additional sources of cancer antigens. We constructed a high-confidence database of translated nuORFs across tissues (nuORFdb) and used it to detect 3,555 translated nuORFs from MHC-I immunopeptidome mass spectrometry analysis, including peptides that result from somatic mutations in nuORFs of cancer samples as well as tumor-specific nuORFs translated in melanoma, chronic lymphocytic leukemia and glioblastoma. NuORFs are an unexplored pool of MHC-I-presented, tumor-specific peptides with potential as immunotherapy targets.
Author Info: (1) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Flagship Labs 69, Cambridge, MA, USA. (2) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (3) Broad Institute of
Author Info: (1) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Flagship Labs 69, Cambridge, MA, USA. (2) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (3) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (4) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (5) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. (6) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (7) Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA. Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (8) Harvard University, Cambridge, MA, USA. (9) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (11) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (12) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (13) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (16) Phillips Academy, Andover, MA, USA. (17) Harvard University, Cambridge, MA, USA. (18) Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA. (19) Broad Institute of MIT and Harvard, Cambridge, MA, USA. MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA. (20) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (21) Immunitrack, Copenhagen, Denmark. (22) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (23) Broad Institute of MIT and Harvard, Cambridge, MA, USA. MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA. (24) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (25) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Massachusetts General Hospital Cancer Center, Boston, MA, USA. (26) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. The Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA, USA. (27) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (28) Broad Institute of MIT and Harvard, Cambridge, MA, USA. cwu@partners.org. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. cwu@partners.org. Harvard Medical School, Boston, MA, USA. cwu@partners.org. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. cwu@partners.org. (29) Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA. aviv.regev.sc@gmail.com. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. aviv.regev.sc@gmail.com. Genentech, South San Francisco, CA, USA. aviv.regev.sc@gmail.com.
