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

Patrick C Lee, Susan Klaeger, Phuong M Le, Keegan Korthauer, Jingwei Cheng, Varsha Ananthapadmanabhan, Thomas C Frost, Jonathan D Stevens, Alan Yl Wong, J Bryan Iorgulescu, Anna Y Tarren, Vipheaviny A Chea, Isabel P Carulli, Camilla K Lemvigh, Christina B Pedersen, Ashley K Gartin, Siranush Sarkizova, Kyle T Wright, Letitia W Li, Jason NomburgShuqiang Li, Teddy Huang, Xiaoxi Liu, Lucas Pomerance, Laura M Doherty, Annie M Apffel, Luke J Wallace, Suzanna Rachimi, Kristen D Felt, Jacquelyn O Wolff, Elizabeth Witten, Wandi Zhang, Donna Neuberg, William J Lane, Guanglan Zhang, Lars R Olsen, Manisha Thakuria, Scott J Rodig, Karl R Clauser, Gabriel J Starrett, John G Doench, Sara J Buhrlage, Steven A Carr, James A DeCaprio, Catherine J Wu, Derin B Keskin

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.

OriginalsprogEngelsk
Artikelnummere151666
TidsskriftThe Journal of clinical investigation
Vol/bind132
Udgave nummer13
ISSN0021-9738
DOI
StatusUdgivet - 1 jul. 2022

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