Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma
Patrick C. Lee, … , Catherine J. Wu, Derin B. Keskin
Patrick C. Lee, … , Catherine J. Wu, Derin B. Keskin
Published July 1, 2022
Citation Information: J Clin Invest. 2022;132(13):e151666. https://doi.org/10.1172/JCI151666.
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Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma

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.

Authors

Patrick C. Lee, Susan Klaeger, Phuong M. Le, Keegan Korthauer, Jingwei Cheng, Varsha Ananthapadmanabhan, Thomas C. Frost, Jonathan D. Stevens, Alan Y.L. 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

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Figure 1

Generation of patient-derived MCC lines that exhibit classic MCC features and recapitulate the low HLA-I expression of their corresponding tumors.

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Generation of patient-derived MCC lines that exhibit classic MCC feature...
(A) IHC of 2 MCC lines stained for MCC markers SOX2 and CK20 (original magnification, ×20). (B) CoMut plot displaying the top 50 most frequently mutated genes across 7 MCC tumor and cell line pairs. (C) Unsupervised hierarchical clustering of RNA-Seq data from 9 MCC patient tumors and corresponding cell lines. Heatmaps were constructed using a distance matrix on variance-stabilizing (VS) transformed expression values. Top track: Quantification of transcript reads mapping to the MCPyV genome. (D) HLA-I flow cytometry in 11 MCC lines, both at baseline (pink bars) and in response to IFN-γ (red bars), compared with isotype control (white bars). The black line plot indicates the percentage of tumor cells positive for HLA-I by IHC of the original tumor. (E) IHC of MCC tumor archival samples. Left: Summary of the percentage of MCC cells that are HLA-I positive within available pretreatment (n = 6) and post-treatment (n = 9) tumor samples (see Table 1 for prior treatments). MCC cell lines were derived from post-treatment samples. Right: Representative IHC images of 2 HLA-I–low tumors, MCC-301 and MCC-336, stained for HLA class I (brown) with SOX2 costain (red) to identify MCC cells. Lymphocytes and endothelial cells served as internal controls that are SOX2 negative and HLA-I positive. Scale bar: 50 μm.