期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 132, 期 13, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI151666
关键词
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资金
- National Cancer Institute (NCI) Cancer Center Support Grant [NIH 5P30CA006516]
- NCI [1R01CA155010, U24CA224331, R01HL131768]
- NIH/NCI [K12CA090354, R21CA216772-01A1]
- Cancer Center Support Grant [5P30CA006516]
- Parker Institute of CancerImmunotherapy
- G. Harold and Leila Y. Mathers Foundation
- Koch Institute for Integrative Cancer Research at MIT
- Dana-Farber/Harvard Cancer Center
- Howard Hughes Medical Institute Medical Research Fellows Program
- US Public Health Service grants [R50CA243777, R35CA232128, R01CA173023, P01CA203655]
- Claudia Adams Barr Program for Innovative Cancer Research
- BC Children's Hospital Research Institute (BCCHRI) Investigator Grant Award Program
- BCCHRI Establishment Award
- Provincial Health Services Authority
- Children's & Women's Health Centre of BC
- BC Children's Hospital Foundation
- Conquer Cancer Foundation/Sontag Foundation
- NCI Clinical Proteomic Tumor Analysis Consortium [NIH/NCI U24CA210986, NIH/NCI U01CA214125]
- [NCISPORE-2P50CA101942-11A1]
This study reveals transcriptional suppression of HLA-I antigen presentation in Merkel cell carcinoma and identifies MYCL, PRC1.1, and USP7 as regulators in this process.
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.
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