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

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. ; Dawson, Mark A.

Cancer cell, 2019-10, Vol.36 (4), p.385-401.e8 [Periódico revisado por pares]

United States: Elsevier Inc

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An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer
Autor: 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. ; Dawson, Mark A.
Assuntos: Animals ; antigen presentation ; 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 ; bivalency ; cancer ; Cell Line, Tumor ; DNA Methylation - immunology ; Down-Regulation - drug effects ; Down-Regulation - genetics ; Down-Regulation - immunology ; Drug Resistance, Neoplasm - genetics ; epigenetic repression ; Epigenetic Repression - drug effects ; Epigenetic Repression - immunology ; EZH2 ; 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 ; histone methyltransferase ; Humans ; immune evasion ; immunotherapy ; MHC class I ; Mice ; Middle Aged ; Neoplasms - drug therapy ; Neoplasms - genetics ; Neoplasms - immunology ; Neoplasms - pathology ; polycomb ; 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
É parte de: Cancer cell, 2019-10, Vol.36 (4), p.385-401.e8
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These authors contributed equally
Descrição: 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. [Display omitted] •PRC2 maintains bivalency at MHC-I antigen-processing genes silencing MHC-I expression•Cancer cells co-opt this conserved, lineage-specific PRC2 function to evade T cells•Pharmacological inhibition of PRC2 in MHC-I low cancers restores anti-tumor immunity•Immunotherapy resistance may arise via non-genomic routes that exploit PRC2 activity Burr et al. show that cancer cells co-opt PRC2 to evade immune surveillance. PRC2 maintains bivalency at the promoters of MHC-I antigen-processing pathway (MHC-I APP) genes to repress their basal and cytokine-activated expression. Inhibition of PRC2 restores the MHC-I APP and T cell-mediated anti-tumor immunity.
Editor: United States: Elsevier Inc
Idioma: Inglês

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

United States: Elsevier Inc

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