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. Shukla; Sune Justesen; Pavan Bachireddy; Manolis Kellis; Gad Getz; Nir Hacohen; Derin B. Keskin; Steven A. Carr; Catherine J. Wu; Aviv Regev

doi:10.1038/s41587-021-01021-3

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 journal › Article › peer-review

110 Scopus citations

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.

Original language	English (US)
Pages (from-to)	209-217
Number of pages	9
Journal	Nature biotechnology
Volume	40
Issue number	2
DOIs	https://doi.org/10.1038/s41587-021-01021-3
State	Published - Feb 2022
Externally published	Yes

ASJC Scopus subject areas

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Molecular Medicine
Biomedical Engineering

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10.1038/s41587-021-01021-3

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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., Chen, S., Chow, Y. T., Ji, Z., Jungreis, I., ... Regev, A. (2022). Unannotated proteins expand the MHC-I-restricted immunopeptidome in cancer. Nature biotechnology, 40(2), 209-217. https://doi.org/10.1038/s41587-021-01021-3

Ouspenskaia, T, Law, T, Clauser, KR, Klaeger, S, Sarkizova, S, Aguet, F, Li, B, Christian, E, Knisbacher, BA, Le, PM, Hartigan, CR, Keshishian, H, Apffel, A, Oliveira, G, Zhang, W, Chen, S, Chow, YT, Ji, Z, Jungreis, I, Shukla, SA, Justesen, S, Bachireddy, P, Kellis, M, Getz, G, Hacohen, N, Keskin, DB, Carr, SA, Wu, CJ & Regev, A 2022, 'Unannotated proteins expand the MHC-I-restricted immunopeptidome in cancer', Nature biotechnology, vol. 40, no. 2, pp. 209-217. https://doi.org/10.1038/s41587-021-01021-3

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title = "Unannotated proteins expand the MHC-I-restricted immunopeptidome in cancer",

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

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doi = "10.1038/s41587-021-01021-3",

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AU - Sarkizova, Siranush

AU - Aguet, François

AU - Li, Bo

AU - Christian, Elena

AU - Knisbacher, Binyamin A.

AU - Le, Phuong M.

AU - Hartigan, Christina R.

AU - Keshishian, Hasmik

AU - Apffel, Annie

AU - Oliveira, Giacomo

AU - Zhang, Wandi

AU - Chen, Sarah

AU - Chow, Yuen Ting

AU - Ji, Zhe

AU - Jungreis, Irwin

AU - Shukla, Sachet A.

AU - Justesen, Sune

AU - Bachireddy, Pavan

AU - Kellis, Manolis

AU - Getz, Gad

AU - Hacohen, Nir

AU - Keskin, Derin B.

AU - Carr, Steven A.

AU - Wu, Catherine J.

AU - Regev, Aviv

PY - 2022/2

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

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