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Systematic evaluation and modulation of HLA class I downregulation in Merkel cell carcinoma

ABSTRACT: Lee PC, Klaeger S, Le PM, Korthauer K, Cheng J, Wong A, Tarren A, Lemvigh C, Sarkizova S, Li L, Frost TC, Nomburg J, Liu X, Pomerance L, Doherty L, Witten E, Zhang W, Apffel A, Wallace L, Neuberg D, Olsen L, Thakuria M, Clauser K, Starrett G, Doench J, Buhrlage SJ, Carr SA, DeCaprio JA, Wu CJ, Keskin DB. 2021 Viruses avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I (HLA I) antigen presentation. Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer often caused by the Merkel cell polyomavirus (MCPyV) that exhibits low HLA class I surface expression. Through the characterization of 11 newly generated MCC cell lines, we identified multiple class I defects including transcriptional suppression of HLA I genes and NLRC5 alterations. To systematically identify regulators of HLA I loss in MCC, we performed parallel genome-scale gain- and loss-of-function screens in an MCPyV-positive line and identified the noncanonical Polycomb repressive complex PRC1.1 and MYCL as HLA I suppressors. Both hits interact with MCPyV viral antigens, and pharmacologic inhibition of PRC1.1 component USP7 resulted in HLA I upregulation. These findings establish a mechanism for MCPyV-mediated HLA class I suppression and identify therapeutic targets for HLA restoration in MCC.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive Plus

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Steven A. Carr

PROVIDER: MSV000087251 | MassIVE | Tue Apr 20 20:15:00 BST 2021

SECONDARY ACCESSION(S): PXD025501

REPOSITORIES: MassIVE

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Project description:Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer with neuroendocrine features. Although the role of epigenetic in tumorigenesis has been documented in most type of cancer, it is overlooked in MCC. The treatment options for MCC is limited and the five-year survival rate remains as low as 33%. In addition, recent studies have suggested multiple mechanisms of epigenetic dysregulation that may contribute to loss H3K27me3 and the tumorigenesis in MCC but not well studied. In this study, we conducted DNA methylation analysis of an existing retrospective cohort of clinically annotated MCC samples, which included samples from 8 primary tumors, three metastatic skin tumors, four metastatic lymph node tumors, and five paired normal tissue samples. Global DNA methylation profile was performed using Illumina Infinium MethylationEPIC array. Two MCC cell lines were also analyzed for DNA methylation and gene expression (RNA-seq) to confirm the correlation between DNA methylation and gene expression for MCC. Our analysis revealed 24,497 loci (14,456 genes) that showed significantly different DNA methylation pattern in the four groups (ANOVA p-value < 0.05 and standard deviation of mean of groups > 0.25) namely adjacent normal, primary tumor, metastatic skin, and metastatic lymph node in MCC patients. By GO terms analysis, the genes correlated with DNA methylation alteration associated with nervous system, cell adhesion, signal transduction, and development pathways. We also observed 870 probes differentially methylated in MCPyV positive and MCPyV negative tumor (FDR adjusted p-value < 0.05 and delta change greater than 0.4 or less than -0.4). Furthermore, using expression and DNA methylation data from two MCC cell lines (MS1 and MCC13) as validation, we identified 964 MCC specific genes directly regulated by DNA methylation either at promoter or gene body, which are highly enriched in nervous system related pathways. By this approach, we not only identify DNA methylation markers for MCC and MCPyV status but also genes regulated by DNA methylation in MCC, MCPyV status, and neuroendocrine features. Most importantly, our results may also suggest overexpression of KDM6B and EZHIP by loss of DNA methylation in their promoter may contribute to loss of H3K27me3 in MCC. In addition, we observed the DNA methylation profile of MS1 resembled MCC patient sample, while DNA methylation profile of MCC13 cell line was similar to small cell lung carcinoma (SCLC), which suggested that MCC13 cell line may originally come from SCLC. Taken together, we have demonstrated dramatic DNA methylation alteration along with four unique patterns in normal, primary and metastatic MCC. Our finding provides DNA methylation markers not only for diagnosis or prognosis of MCC and MCPyV status but also correlate gene expression status of MCC specific genes with important functional roles in MCC tumorigenesis, MCPyV expression, neuroendocrine feature and H3K27me3 status. The identification of DNA methylation alteration in MCC also provides foundation for potential implication of epigenetic therapy for MCC patients.

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Systematic evaluation and modulation of HLA class I downregulation in Merkel cell carcinoma

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