1. Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma.
- Author
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Lee PC, Klaeger S, Le PM, Korthauer K, Cheng J, Ananthapadmanabhan V, Frost TC, Stevens JD, Wong AY, Iorgulescu JB, Tarren AY, Chea VA, Carulli IP, Lemvigh CK, Pedersen CB, Gartin AK, Sarkizova S, Wright KT, Li LW, Nomburg J, Li S, Huang T, Liu X, Pomerance L, Doherty LM, Apffel AM, Wallace LJ, Rachimi S, Felt KD, Wolff JO, Witten E, Zhang W, Neuberg D, Lane WJ, Zhang G, Olsen LR, Thakuria M, Rodig SJ, Clauser KR, Starrett GJ, Doench JG, Buhrlage SJ, Carr SA, DeCaprio JA, Wu CJ, and Keskin DB
- 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
- 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.
- Published
- 2022
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