Dataset Information

Systematic evaluation and modulation of HLA class I downregulation in Merkel cell carcinoma

ABSTRACT: Lee PC, Klaeger S, Le PM, Korthauer K, Cheng J, Wong A, Tarren A, Lemvigh C, Sarkizova S, Li L, Frost TC, Nomburg J, Liu X, Pomerance L, Doherty L, Witten E, Zhang W, Apffel A, Wallace L, Neuberg D, Olsen L, Thakuria M, Clauser K, Starrett G, Doench J, Buhrlage SJ, Carr SA, DeCaprio JA, Wu CJ, Keskin DB. 2021 Viruses avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I (HLA I) antigen presentation. Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer often caused by the Merkel cell polyomavirus (MCPyV) that exhibits low HLA class I surface expression. Through the characterization of 11 newly generated MCC cell lines, we identified multiple class I defects including transcriptional suppression of HLA I genes and NLRC5 alterations. To systematically identify regulators of HLA I loss in MCC, we performed parallel genome-scale gain- and loss-of-function screens in an MCPyV-positive line and identified the noncanonical Polycomb repressive complex PRC1.1 and MYCL as HLA I suppressors. Both hits interact with MCPyV viral antigens, and pharmacologic inhibition of PRC1.1 component USP7 resulted in HLA I upregulation. These findings establish a mechanism for MCPyV-mediated HLA class I suppression and identify therapeutic targets for HLA restoration in MCC.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive Plus

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Steven A. Carr

PROVIDER: MSV000087251 | MassIVE | Tue Apr 20 20:15:00 BST 2021

SECONDARY ACCESSION(S): PXD025501

REPOSITORIES: MassIVE

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Systematic evaluation and modulation of HLA class I downregulation in Merkel cell carcinoma

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