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

Cancer Cell. 2019 Oct 14;36(4):385-401.e8. doi: 10.1016/j.ccell.2019.08.008. Epub 2019 Sep 26.

Authors

Marian L Burr¹, Christina E Sparbier², Kah Lok Chan², Yih-Chih Chan³, Ariena Kersbergen⁴, Enid Y N Lam², Elizabeth Azidis-Yates³, Dane Vassiliadis², Charles C Bell², Omer Gilan², Susan Jackson³, Lavinia Tan², Stephen Q Wong², Sebastian Hollizeck², Ewa M Michalak², Hannah V Siddle⁵, Michael T McCabe⁶, Rab K Prinjha⁷, Glen R Guerra², Benjamin J Solomon², Shahneen Sandhu², Sarah-Jane Dawson⁸, Paul A Beavis², Richard W Tothill⁹, Carleen Cullinane², Paul J Lehner¹⁰, Kate D Sutherland¹¹, Mark A Dawson¹²

Affiliations

¹ Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia; Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK. Electronic address: marian.burr@petermac.org.
² Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia.
³ Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000, Australia.
⁴ ACRF Cancer Biology and Stem Cell Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
⁵ Department of Biological Sciences, University of Southampton, Southampton, UK; Institute for Life Sciences, University of Southampton, Southampton, UK.
⁶ Epigenetics Research Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA.
⁷ Epigenetics Research Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA; Epigenetics Research Unit, GlaxoSmithKline, Stevenage, UK.
⁸ Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia; Centre for Cancer Research, University of Melbourne, Parkville, Australia.
⁹ Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia; Centre for Cancer Research, University of Melbourne, Parkville, Australia; Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.
¹⁰ Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
¹¹ ACRF Cancer Biology and Stem Cell Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
¹² Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia; Centre for Cancer Research, University of Melbourne, Parkville, Australia. Electronic address: mark.dawson@petermac.org.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigen Presentation / drug effects
Antigen Presentation / immunology
Antineoplastic Agents, Immunological / pharmacology
Antineoplastic Agents, Immunological / therapeutic use
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Cell Line, Tumor
DNA Methylation / immunology
Down-Regulation / drug effects
Down-Regulation / genetics
Down-Regulation / immunology
Drug Resistance, Neoplasm / genetics
Epigenetic Repression / drug effects
Epigenetic Repression / immunology
Female
Gene Expression Regulation, Neoplastic / drug effects
Gene Expression Regulation, Neoplastic / immunology*
Histocompatibility Antigens Class I / genetics*
Histocompatibility Antigens Class I / immunology
Histocompatibility Antigens Class I / metabolism
Histone Code / drug effects
Humans
Mice
Middle Aged
Neoplasms / drug therapy
Neoplasms / genetics
Neoplasms / immunology*
Neoplasms / pathology
Polycomb Repressive Complex 2 / antagonists & inhibitors
Polycomb Repressive Complex 2 / metabolism*
T-Lymphocytes / immunology
Tumor Escape / drug effects
Tumor Escape / genetics*
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents, Immunological
Histocompatibility Antigens Class I
Polycomb Repressive Complex 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding