期刊
CANCER CELL
卷 36, 期 4, 页码 385-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2019.08.008
关键词
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资金
- Cancer Research UK Clinician Scientist Fellowship [C53779/A20097]
- Leukaemia Foundation Australia Senior Fellowship
- Howard Hughes Medical Institute International Research Scholarship [55008729]
- Peter and Julie Alston Centenary fellowship
- Wellcome Trust Principal Research Fellowship [101835/Z/13/Z]
- Peter MacCallum Postgraduate Scholarship
- NHMRC Postgraduate Scholarship
- Maddie Riewoldt's Vision [064728]
- Victorian Cancer Agency
- CSL Centenary fellowship
- National Breast Cancer Foundation Fellowship [ECF17-005]
- Addenbrooke's Charitable Trust
- NIHR Cambridge BRC
- NHMRC [1085015, 1106444, 1128984]
- National Health and Medical Research Council of Australia [1128984, 1085015, 1106444] Funding Source: NHMRC
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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