An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer

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

doi:10.1016/j.ccell.2019.08.008

An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer

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

^*Corresponding author for this work

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

526 Citations (Scopus)

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.

Original language	English
Pages (from-to)	385-401.e8
Journal	Cancer Cell
Volume	36
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2019.08.008
Publication status	Published - 14 Oct 2019
Externally published	Yes

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Burr, M. L., Sparbier, C. E., Chan, K. L., Chan, Y. C., Kersbergen, A., Lam, E. Y. N., Azidis-Yates, E., Vassiliadis, D., Bell, C. C., Gilan, O., Jackson, S., Tan, L., Wong, S. Q., Hollizeck, S., Michalak, E. M., Siddle, H. V., McCabe, M. T., Prinjha, R. K., Guerra, G. R., ... Dawson, M. 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. https://doi.org/10.1016/j.ccell.2019.08.008

@article{ea251acf1c8442cc920050eefb297b6f,

title = "An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer",

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.",

keywords = "EZH2, MHC class I, antigen presentation, bivalency, cancer, epigenetic repression, histone methyltransferase, immune evasion, immunotherapy, polycomb",

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

note = "Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = oct,

day = "14",

doi = "10.1016/j.ccell.2019.08.008",

language = "English",

volume = "36",

pages = "385--401.e8",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "4",

}

Burr, ML, Sparbier, CE, Chan, KL, Chan, YC, Kersbergen, A, Lam, EYN, Azidis-Yates, E, Vassiliadis, D, Bell, CC, Gilan, O, Jackson, S, Tan, L, Wong, SQ, Hollizeck, S, Michalak, EM, Siddle, HV, McCabe, MT, Prinjha, RK, Guerra, GR, Solomon, BJ, Sandhu, S, Dawson, SJ, Beavis, PA, Tothill, RW, Cullinane, C, Lehner, PJ, Sutherland, KD & Dawson, MA 2019, 'An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer', Cancer Cell, vol. 36, no. 4, pp. 385-401.e8. https://doi.org/10.1016/j.ccell.2019.08.008

TY - JOUR

T1 - An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer

AU - Burr, Marian L.

AU - Sparbier, Christina E.

AU - Chan, Kah Lok

AU - Chan, Yih Chih

AU - Kersbergen, Ariena

AU - Lam, Enid Y.N.

AU - Azidis-Yates, Elizabeth

AU - Vassiliadis, Dane

AU - Bell, Charles C.

AU - Gilan, Omer

AU - Jackson, Susan

AU - Tan, Lavinia

AU - Wong, Stephen Q.

AU - Hollizeck, Sebastian

AU - Michalak, Ewa M.

AU - Siddle, Hannah V.

AU - McCabe, Michael T.

AU - Prinjha, Rab K.

AU - Guerra, Glen R.

AU - Solomon, Benjamin J.

AU - Sandhu, Shahneen

AU - Dawson, Sarah Jane

AU - Beavis, Paul A.

AU - Tothill, Richard W.

AU - Cullinane, Carleen

AU - Lehner, Paul J.

AU - Sutherland, Kate D.

AU - Dawson, Mark A.

PY - 2019/10/14

Y1 - 2019/10/14

N2 - 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.

AB - 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.

KW - EZH2

KW - MHC class I

KW - antigen presentation

KW - bivalency

KW - cancer

KW - epigenetic repression

KW - histone methyltransferase

KW - immune evasion

KW - immunotherapy

KW - polycomb

UR - https://www.scopus.com/pages/publications/85072915038

U2 - 10.1016/j.ccell.2019.08.008

DO - 10.1016/j.ccell.2019.08.008

M3 - Article

SN - 1535-6108

VL - 36

SP - 385-401.e8

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -

An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer

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