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.

中文翻译：

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默克尔细胞癌中病毒和表观遗传 HLA I 类抑制的逆转


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、HLA-I 低、神经内分泌皮肤癌，通常由默克尔细胞多瘤病毒 (MCPyV) 引起。通过对 11 种新产生的 MCC 患者来源的细胞系进行表征，我们发现了几种 I 类抗原呈递基因的转录抑制。为了系统地识别 MCC 中 HLA-I 丢失的调节因子，我们在源自患者的 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，并鉴定了 MYCL 和非典型 Polycomb 抑制复合物1.1 (PRC1.1) 作为 HLA-I 阻遏物。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 成分 USP7 作为恢复 MCC 中 HLA-I 表达的药理学靶点。