Journal Article

Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma

Korthauer, Keegan, Iorgulescu, Bryan, Wong, Alan Y.L, Le, Phuong M, Stevens, Jonathan D, Lee, Patrick C, Klaeger, Susan, Cheng, Jingwei, Ananthapadmanabhan, Varsah, Frost, Thomas C

2022

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Antigen presentation / Biomedical research / Biopsy / Cancer / Development and progression / Drug therapy / Epigenetics / Genomes / Health aspects / Histocompatibility antigen HLA / Histocompatibility antigens / HLA histocompatibility antigens / Immunosurveillance / Immunotherapy / Merkel cell carcinoma / Mutation / Neuroendocrine tumors / Physiological aspects / Polycomb group proteins / Repressors / Skin cancer / Stem cells / Tumors