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Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2022 Jul 01; Vol. 132 (13). - Publication Year :
- 2022
-
Abstract
- 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.
- Subjects :
- Antigens, Viral, Tumor genetics
Antigens, Viral, Tumor metabolism
Epigenesis, Genetic
Humans
Ubiquitin-Specific Peptidase 7 metabolism
Carcinoma, Merkel Cell genetics
Carcinoma, Merkel Cell pathology
Merkel cell polyomavirus genetics
Merkel cell polyomavirus metabolism
Polyomavirus Infections genetics
Skin Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 132
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 35775490
- Full Text :
- https://doi.org/10.1172/JCI151666