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J Clin Invest DOI:10.1172/JCI151666

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

Publication TypeJournal Article
Year of Publication2022
AuthorsLee, PC, Klaeger, S, Le, PM, Korthauer, K, Cheng, J, Ananthapadmanabhan, V, Frost, TC, Stevens, JD, Wong, AYl, J Iorgulescu, B, 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, Keskin, DB
JournalJ Clin Invest
Volume132
Issue13
Date Published2022 07 01
ISSN1558-8238
KeywordsAntigens, Viral, Tumor, Carcinoma, Merkel Cell, Epigenesis, Genetic, Humans, Merkel cell polyomavirus, Polyomavirus Infections, Skin Neoplasms, Ubiquitin-Specific Peptidase 7
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.

DOI10.1172/JCI151666
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/35775490?dopt=Abstract

Alternate JournalJ Clin Invest
PubMed ID35775490
PubMed Central IDPMC9246387
Grant ListU24 CA224331 / CA / NCI NIH HHS / United States
R01 HL131768 / HL / NHLBI NIH HHS / United States
R21 CA216772 / CA / NCI NIH HHS / United States
R50 CA243777 / CA / NCI NIH HHS / United States
R35 CA232128 / CA / NCI NIH HHS / United States
R01 CA173023 / CA / NCI NIH HHS / United States
P01 CA203655 / CA / NCI NIH HHS / United States
K12 CA090354 / CA / NCI NIH HHS / United States
U24 CA210986 / CA / NCI NIH HHS / United States
U01 CA214125 / CA / NCI NIH HHS / United States