Unannotated proteins expand the MHC-I-restricted immunopeptidome in cancer

Tamara Ouspenskaia, Travis Law, Karl R. Clauser, Susan Klaeger, Siranush Sarkizova, François Aguet, Bo Li, Elena Christian, Binyamin A. Knisbacher, Phuong M. Le, Christina R. Hartigan, Hasmik Keshishian, Annie Apffel, Giacomo Oliveira, Wandi Zhang, Sarah Chen, Yuen Ting Chow, Zhe Ji, Irwin Jungreis, Sachet A. ShuklaSune Justesen, Pavan Bachireddy, Manolis Kellis, Gad Getz, Nir Hacohen, Derin B. Keskin, Steven A. Carr, Catherine J. Wu, Aviv Regev

Research output: Contribution to journalArticlepeer-review

95 Scopus citations


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.

Original languageEnglish
Pages (from-to)209-217
Number of pages9
JournalNature Biotechnology
Issue number2
StatePublished - Feb 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.


Dive into the research topics of 'Unannotated proteins expand the MHC-I-restricted immunopeptidome in cancer'. Together they form a unique fingerprint.

Cite this