Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma

Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I-low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterizati...

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Bibliographic Details
Published in:The Journal of clinical investigation 2022-07, Vol.132 (13), p.1-16
Main Authors: Lee, Patrick C, Klaeger, Susan, Le, Phuong M, Korthauer, Keegan, Cheng, Jingwei, Ananthapadmanabhan, Varsah, Frost, Thomas C, Stevens, Jonathan D, Wong, Alan Y.L, Iorgulescu, Bryan
Format: Article
Language:English
Subjects:
Antigen presentation
Biomedical research
Biopsy
Cancer
Development and progression
Drug therapy
Epigenetics
Genomes
Health aspects
Histocompatibility antigen HLA
Histocompatibility antigens
HLA histocompatibility antigens
Immunosurveillance
Immunotherapy
Merkel cell carcinoma
Mutation
Neuroendocrine tumors
Physiological aspects
Polycomb group proteins
Repressors
Skin cancer
Stem cells
Tumors
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Summary:Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I-low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of several class I antigen presentation genes. To systematically identify regulators of HLA-I loss in MCC, we performed parallel, genome-scale, gain- and loss-of-function screens in a patient-derived MCPyV-positive cell line and identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. We observed physical interaction of MYCL with the MCPyV small T viral antigen, supporting a mechanism of virally mediated HLA-I suppression. We further identify the PRC1.1 component USP7 as a pharmacologic target to restore HLA-I expression in MCC.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCn51666