Journal article
Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma
Dana-Farber Cancer Institute1
National Institutes of Health2
Technical University of Denmark3
Broad Institute of Harvard University and Massachusetts Institute of Technology4
University of British Columbia5
Harvard University6
Brigham and Women’s Hospital7
Single Cell Omics, Bioinformatics, Department of Health Technology, Technical University of Denmark8
Bioinformatics, Department of Health Technology, Technical University of Denmark9
Department of Health Technology, Technical University of Denmark10
Boston University11
...and 1 moreCancers 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.
| Language: | English |
|---|---|
| Publisher: | American Society for Clinical Investigation |
| Year: | 2022 |
| ISSN: | 15588238 and 00219738 |
| Types: | Journal article |
| DOI: | 10.1172/JCI151666 |
| ORCIDs: | 0000-0001-9291-6179 , 0000-0002-0074-5163 , 0000-0001-8639-1572 , 0000-0002-4565-1654 , 0000-0003-3832-0897 , 0000-0002-6909-1460 , 0000-0002-7855-1000 , 0000-0003-1405-3667 , 0000-0003-2155-5710 , 0000-0002-6592-8710 , 0000-0002-5772-8743 , Pedersen, Christina B. , 0000-0001-8072-6650 , 0000-0003-2816-0260 , 0000-0001-7807-8658 , 0000-0002-8171-5109 , 0000-0002-2209-3944 , 0000-0001-7294-8683 , 0000-0003-3257-9056 , 0000-0003-2566-3145 , 0000-0002-1097-5229 , 0000-0001-6010-490X , Olsen, Lars R. , 0000-0001-5871-5306 , 0000-0002-3707-9889 , 0000-0002-0896-167X and 0000-0002-8496-6181 |
