Lee et al. generated and characterized 11 MCC patient-derived cell lines and demonstrated the loss of HLA-I surface expression and multiple class I pathway genes. Complementary genome-scale gain- and loss-of-function screens in a polyoma virus-positive line identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. ST-MYCL-EP400 complex components interacted with MCPyV small T viral antigen and occupied the PRC1.1 gene’s USP7 and PCGF1 promoters to suppress HLA-I surface expression. Pharmacologic inhibition of the PRC1.1 component USP7 was able to restore HLA-I surface expression.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Harvard Medical School, Boston, Massachusetts, USA. (2) Broad Institute of MIT and Har
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Harvard Medical School, Boston, Massachusetts, USA. (2) Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. (4) Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada. BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada. (5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, New Hampshire, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Harvard Medical School, Boston, Massachusetts, USA. (7) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA. (8) Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Harvard Medical School, Boston, Massachusetts, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Harvard Medical School, Boston, Massachusetts, USA. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. (12) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. (13) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. (14) Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark. (15) Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark. Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA. (17) Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA. (18) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Harvard Medical School, Boston, Massachusetts, USA. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. (19) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. (20) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA. (21) Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. (22) Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. (23) Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Department of Biological Chemistry and Molecular Pharmacology. (24) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Department of Immunology, and. (25) Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Department of Biological Chemistry and Molecular Pharmacology. Department of Systems Biology and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts, USA. (26) Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. (27) Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. (28) Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. (29) Center for Immuno-Oncology and. (30) Center for Immuno-Oncology and. (31) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. (32) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. (33) Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. (34) Harvard Medical School, Boston, Massachusetts, USA. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. (35) Department of Computer Science, Metropolitan College, Boston University, Boston, Massachusetts, USA. (36) Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark. Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. (37) Harvard Medical School, Boston, Massachusetts, USA. Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Merkel Cell Carcinoma Center of Excellence, Dana-Farber/Brigham Cancer Center, Boston, Massachusetts, USA. (38) Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. Center for Immuno-Oncology and. (39) Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. (40) Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA. (41) Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. (42) Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Department of Biological Chemistry and Molecular Pharmacology. (43) Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. (44) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Harvard Medical School, Boston, Massachusetts, USA. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA. Merkel Cell Carcinoma Center of Excellence, Dana-Farber/Brigham Cancer Center, Boston, Massachusetts, USA. (45) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Harvard Medical School, Boston, Massachusetts, USA. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. (46) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Harvard Medical School, Boston, Massachusetts, USA. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark. Department of Computer Science, Metropolitan College, Boston University, Boston, Massachusetts, USA.
