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^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

126 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

Funding

We thank K. Gosik and R. Herbst for their help with the statistical analysis. We thank D. Fu for her help with the nonmetric multidimensional scaling analysis. We thank E. Hodis and J. Kwon for providing cultured primary melanocytes. We thank K.L. Ligon for providing the GBM cell line. We thank L. Gaffney for help with figure preparation. Work was supported by the Klarman Cell Observatory and HHMI (A.R.), NIH grant nos. NCI-1R01CA155010-02 (to C.J.W.), NHLBI-5R01HL103532-03 (to C.J.W.), NIH/ NCI R21 CA216772-01A1 (to D.B.K.), NCI-SPORE-2P50CA101942-11A1 (to D.B.K), NHGRI T32HG002295 and NIH/NCI T32CA207021 (to S.S.), NCI R50CA211482 (to S.A.S.), NHGRI U41HG007234 and R01 HG004037 (to I.J.), NCI Clinical Proteomic Tumor Analysis Consortium grant nos. NIH/NCI U24-CA210986 and NIH/NCI U01 CA214125 (to S.A.C.) and NIH/NCI U24CA210979 (to D.R. Mani and G. Getz). This work was supported in part by The G. Harold and Leila Y. Mathers Foundation and the Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center. C.J.W. is a scholar of the Leukemia and Lymphoma Society, and is supported in part by the Parker Institute for Cancer Immunotherapy. S.K. is a Cancer Research Institute/Hearst Foundation fellow. T.O. is a Leukemia and Lymphoma Society Fellow. B.A.K. is supported by a long-term EMBO fellowship (ALTF 14-2018). P.B. is supported by an Amy Strelzer Manasevit Grant and an American Society of Hematology Scholar Award. G.O. is supported by a postdoctoral fellowship sponsored by the American-Italian Cancer Foundation.

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

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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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year = "2022",

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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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AU - Law, Travis

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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.

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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

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N2 - 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.

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

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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