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Background and aims: Loss of human leukocyte antigen class I (HLA-I) is a striking feature of Merkel cell carcinoma (MCC) and a well-characterized mechanism of immune escape. However, HLA-I can be upregulated in MCC with IFN-γ, histone deacetylase inhibitors, or demethylating agents, suggestive of epigenetic repression of class I antigen presentation genes. We hypothesized that restoration of HLA-I should increase MCC immunogenicity and facilitate viral epitope presentation. Moreover, given the paucity of mutations in Merkel cell polyomavirus-positive (MCPyV+) MCC in particular, we suspected that viral antigen-mediated signaling may suppress HLA-I surface expression in MCPyV+ MCC. Methods: Current MCC lines are limited in number and may not faithfully recapitulate their primary tumors. Therefore, we developed an approach to establish 11 MCC lines directly from tumor biopsies and patient-derived xenografts (PDX). We characterized class I APM genes in these MCC lines at the genomic, transcriptomic, and proteomic level. Using our improved sample preparation and data acquisition strategies, we profiled the immunopeptidomes of 4 MCC tumors. We then interrogated an MCPyV+ line through genome-scale gain- and loss-of-function screens to identify regulators of HLA-I. Results: These new MCC lines were highly correlated with original tumors by WES, RNA-seq, proteome, and immunopeptidome analysis. We identified three HLA I-presented peptides derived from the MCPyV large T antigen in two lines after IFN-γ treatment, one of which was evaluated in ELISpot assays and found to be immunogenic. Subsequently, our genome-scale screens identified MYCL and the noncanonical Polycomb repressive complex 1.1 (PRC1.1) as novel regulators of HLA-I. We observed physical interaction of MYCL with the MCPyV Small T viral antigen (sT). We further demonstrate that pharmacologic inhibition of PRC1.1 component USP7 upregulates HLA-I expression. Conclusions: The identification of viral epitopes within MCC immunopeptidomes after IFN-γ-induced class I upregulation supports the development of MCC vaccine immunotherapies and provides further motivation to discover methods of HLA-I restoration in MCC. We identified MYCL and PRC1.1 as novel repressors of HLA-I in MCC and validated USP7 as a pharmacologic target to upregulate HLA-I. The physical interaction of MYCL and MCPyV sT suggests a mechanism of virally mediated HLA-I suppression.