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

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 characterizati...

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Detalles Bibliográficos
Autores principales: Lee, Patrick C., Klaeger, Susan, Le, Phuong M., Korthauer, Keegan, Cheng, Jingwei, Ananthapadmanabhan, Varsha, Frost, Thomas C., Stevens, Jonathan D., Wong, Alan Y.L., Iorgulescu, J. Bryan, Tarren, Anna Y., Chea, Vipheaviny A., Carulli, Isabel P., Lemvigh, Camilla K., Pedersen, Christina B., Gartin, Ashley K., Sarkizova, Siranush, Wright, Kyle T., Li, Letitia W., Nomburg, Jason, Li, Shuqiang, Huang, Teddy, Liu, Xiaoxi, Pomerance, Lucas, Doherty, Laura M., Apffel, Annie M., Wallace, Luke J., Rachimi, Suzanna, Felt, Kristen D., Wolff, Jacquelyn O., Witten, Elizabeth, Zhang, Wandi, Neuberg, Donna, Lane, William J., Zhang, Guanglan, Olsen, Lars R., Thakuria, Manisha, Rodig, Scott J., Clauser, Karl R., Starrett, Gabriel J., Doench, John G., Buhrlage, Sara J., Carr, Steven A., DeCaprio, James A., Wu, Catherine J., Keskin, Derin B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Research Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9246387/
https://www.ncbi.nlm.nih.gov/pubmed/35775490
http://dx.doi.org/10.1172/JCI151666
Descripción
Sumario: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.

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