Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Harvard Medical School, Boston, Massachusetts, USA.
J Clin Invest. 2022 Jul 1;132(13). doi: 10.1172/JCI151666.
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.
癌症通过一系列机制逃避免疫监视，包括 HLA I 类抗原呈递的改变。默克尔细胞癌（MCC）是一种侵袭性的、HLA-I 低表达的神经内分泌皮肤癌，通常由默克尔细胞多瘤病毒（MCPyV）引起。通过对 11 种新生成的 MCC 患者衍生细胞系的特征分析，我们发现了几个 I 类抗原呈递基因的转录抑制。为了系统地鉴定 MCC 中 HLA-I 丢失的调节因子，我们在一个患者衍生的 MCPyV 阳性细胞系中进行了平行的、全基因组规模的、增益和缺失功能筛选，并鉴定出 MYCL 和非典型多梳抑制复合物 1.1（PRC1.1）是 HLA-I 的抑制剂。我们观察到 MYCL 与 MCPyV 小 T 病毒抗原的物理相互作用，支持了病毒介导的 HLA-I 抑制的机制。我们进一步鉴定出 PRC1.1 成分 USP7 是恢复 MCC 中 HLA-I 表达的药物靶点。
