Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma.
Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma.
复制标题
默克尔细胞癌中病毒和表观遗传HLA I类抑制的恢复
DOI：
10.1172/jci151666
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发表时间：
2022-07-01
影响因子：
15.9
通讯作者：
Keskin, Derin B.
中科院分区：
文献类型：
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作者：
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.
癌症通过一系列机制避免免疫监视，包括干扰HLA I类抗原呈递。默克尔细胞癌（MCC）是一种侵袭性的、HLA-I低的皮肤神经内分泌癌，通常由默克尔细胞多瘤病毒（MCPyV）引起。通过对11个新产生的MCC患者源性细胞系的表征，我们确定了几个I类抗原呈递基因的转录抑制。为了系统地鉴定MCC中HLA-I损失的调节剂，我们在患者来源的MCPyV阳性细胞系中进行了平行的基因组规模的功能获得和功能丧失筛选，并将MYCL和非典型的Polycomb抑制复合物1.1（PRC1.1）鉴定为HLA-I抑制剂。我们观察到MYCL与MCPyV小T病毒抗原的物理相互作用，支持病毒介导的HLA-I抑制机制。我们进一步确定PRC1.1组分USP 7作为恢复MCC中HLA-I表达的药理学靶点。
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.