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An evolutionarily conserved function of polycomb silences the MHC Class I antigen presentation pathway and enables immune evasion in cancer

An evolutionarily conserved function of polycomb silences the MHC Class I antigen presentation pathway and enables immune evasion in cancer
An evolutionarily conserved function of polycomb silences the MHC Class I antigen presentation pathway and enables immune evasion in cancer

Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP), promoting evasion of T cell-mediated immunity. MHC-I APP gene promoters in MHC-I low cancers harbor bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine-induced upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological MHC-I silencing highlights a conserved mechanism by which cancers arising from these primitive tissues exploit PRC2 activity to enable immune evasion.

antigen presentation, bivalency, cancer, epigenetic repression, EZH2, histone methyltransferase, immune evasion, immunotherapy, MHC class I, polycomb
1535-6108
385-401.e8
Burr, Marian L.
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Sparbier, Christina E.
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Chan, Kah Lok
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Chan, Yih Chih
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Kersbergen, Ariena
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Lam, Enid Y.N.
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Azidis-Yates, Elizabeth
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Vassiliadis, Dane
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Bell, Charles C.
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Gilan, Omer
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Jackson, Susan
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Tan, Lavinia
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Wong, Stephen Q.
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Hollizeck, Sebastian
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Michalak, Ewa M.
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Siddle, Hannah V.
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McCabe, Michael T.
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Prinjha, Rab K.
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Guerra, Glen R.
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Sandhu, Shahneen
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Dawson, Sarah Jane
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Beavis, Paul A.
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Tothill, Richard W.
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Cullinane, Carleen
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Lehner, Paul J.
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Sutherland, Kate D.
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Dawson, Mark A.
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Burr, Marian L.
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Sparbier, Christina E.
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Chan, Kah Lok
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Lam, Enid Y.N.
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Azidis-Yates, Elizabeth
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Vassiliadis, Dane
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Bell, Charles C.
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Gilan, Omer
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Jackson, Susan
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Tan, Lavinia
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Wong, Stephen Q.
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Hollizeck, Sebastian
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Michalak, Ewa M.
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Siddle, Hannah V.
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McCabe, Michael T.
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Prinjha, Rab K.
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Guerra, Glen R.
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Sandhu, Shahneen
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Dawson, Sarah Jane
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Beavis, Paul A.
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Tothill, Richard W.
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Cullinane, Carleen
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Lehner, Paul J.
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Sutherland, Kate D.
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Dawson, Mark A.
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Burr, Marian L., Sparbier, Christina E., Chan, Kah Lok, Chan, Yih Chih, Kersbergen, Ariena, Lam, Enid Y.N., Azidis-Yates, Elizabeth, Vassiliadis, Dane, Bell, Charles C., Gilan, Omer, Jackson, Susan, Tan, Lavinia, Wong, Stephen Q., Hollizeck, Sebastian, Michalak, Ewa M., Siddle, Hannah V., McCabe, Michael T., Prinjha, Rab K., Guerra, Glen R., Solomon, Benjamin J., Sandhu, Shahneen, Dawson, Sarah Jane, Beavis, Paul A., Tothill, Richard W., Cullinane, Carleen, Lehner, Paul J., Sutherland, Kate D. and Dawson, Mark A. (2019) An evolutionarily conserved function of polycomb silences the MHC Class I antigen presentation pathway and enables immune evasion in cancer. Cancer Cell, 36 (4), 385-401.e8. (doi:10.1016/j.ccell.2019.08.008).

Record type: Article

Abstract

Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP), promoting evasion of T cell-mediated immunity. MHC-I APP gene promoters in MHC-I low cancers harbor bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine-induced upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological MHC-I silencing highlights a conserved mechanism by which cancers arising from these primitive tissues exploit PRC2 activity to enable immune evasion.

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Accepted/In Press date: 24 August 2019
e-pub ahead of print date: 26 September 2019
Published date: 14 October 2019
Keywords: antigen presentation, bivalency, cancer, epigenetic repression, EZH2, histone methyltransferase, immune evasion, immunotherapy, MHC class I, polycomb
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Identifiers

Local EPrints ID: 435113
URI: http://eprints.soton.ac.uk/id/eprint/435113
DOI: doi:10.1016/j.ccell.2019.08.008
ISSN: 1535-6108
PURE UUID: 0e928203-2f78-46e8-8617-3bea95e5aaa1
ORCID for Hannah V. Siddle: ORCID iD orcid.org/0000-0003-2906-4385

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Date deposited: 23 Oct 2019 16:30
Last modified: 18 Mar 2024 03:28

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Contributors

Author: Marian L. Burr
Author: Christina E. Sparbier
Author: Kah Lok Chan
Author: Yih Chih Chan
Author: Ariena Kersbergen
Author: Enid Y.N. Lam
Author: Elizabeth Azidis-Yates
Author: Dane Vassiliadis
Author: Charles C. Bell
Author: Omer Gilan
Author: Susan Jackson
Author: Lavinia Tan
Author: Stephen Q. Wong
Author: Sebastian Hollizeck
Author: Ewa M. Michalak
Author: Hannah V. Siddle ORCID iD
Author: Michael T. McCabe
Author: Rab K. Prinjha
Author: Glen R. Guerra
Author: Benjamin J. Solomon
Author: Shahneen Sandhu
Author: Sarah Jane Dawson
Author: Paul A. Beavis
Author: Richard W. Tothill
Author: Carleen Cullinane
Author: Paul J. Lehner
Author: Kate D. Sutherland
Author: Mark A. Dawson

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