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

J Clin Invest
Authors
Keywords
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.

Year of Publication
2022
Journal
J Clin Invest
Volume
132
Issue
13
Date Published
2022 07 01
ISSN
1558-8238
DOI
10.1172/JCI151666
PubMed ID
35775490
PubMed Central ID
PMC9246387
Links
Grant list
U24 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