Identifying Novel Modulators of MHC I Expression in Merkel Cell Carcinoma Through Genome-Scale Screens

Abstract

Loss of major histocompatibility complex class I (MHC I) is an important mechanism by which cancer cells evade immune surveillance. Decreased MHC I expression has been reported in 16% to 80% of lesions across different cancers and has been shown to correlate with poor prognosis and resistance to immunotherapy. MHC I loss can be caused by irreversible (somatic mutations, loss of heterozygosity) or reversible (transcriptional) downregulation of one or multiple genes within the class I antigen presentation pathway. While agents such as interferons, histone deacetylase inhibitors, or demethylating agents can upregulate MHC I, they lack specificity. Moreover, the often coordinated downregulation of several MHC I pathway genes across cancers suggests the presence of a regulatory epigenetic program that has yet to be characterized. To study this phenomenon of reversible MHC I loss, I used Merkel cell carcinoma (MCC) as a model system. MCC is a rare but aggressive neuroendocrine skin cancer, 80% of which is caused by the Merkel cell polyomavirus. Importantly, MHC I downregulation is prevalent and occurs in 84% of MCC tumors. Using a series of patient-derived MCC cell lines, I characterized mechanisms of MHC I loss in MCC, and then conducted paired genome-scale CRISPR-knockout and open reading frame (ORF) gain-of-function screens to identify regulators of the MHC I pathway.