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

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DOI

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  • 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 Nomburg
  • Shuqiang 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
Vis graf over relationer

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

ID: 79165251