Lee et al. generated and characterized 11 MCC patient-derived cell lines and demonstrated the loss of HLA-I surface expression and multiple class I pathway genes. Complementary genome-scale gain- and loss-of-function screens in a polyoma virus-positive line identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. ST-MYCL-EP400 complex components interacted with MCPyV small T viral antigen and occupied the PRC1.1 gene’s USP7 and PCGF1 promoters to suppress HLA-I surface expression. Pharmacologic inhibition of the PRC1.1 component USP7 was able to restore HLA-I surface expression.
Contributed by Shishir Pant
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.