Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma
July 5, 2022
The Journal of Clinical Investigation
July 5, 2022Download PDF
In addition to developing another 11 Merkel cell carcinoma cell lines for research, this team from Dana-Farber Cancer Institute has helped unravel how MCC hides from the immune system. While it has been known for over a decade that MCC suppresses proteins called “HLA Class I” (necessary for the immune system to ‘see’ invaders like viruses), this study provides new insight on how MCC accomplishes this. Indeed, a cancer-promoting protein called Myc-L can be co-opted by the virus or directly mutated by UV to help hide the cancer from immune attack. The authors suggest several mechanisms that may help expose MCC to immune attack.
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.