Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma
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 characterizati...
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-07-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI151666 |
| _version_ | 1811326469596512256 |
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| author | Patrick C. Lee Susan Klaeger Phuong M. Le Keegan Korthauer Jingwei Cheng Varsha Ananthapadmanabhan Thomas C. Frost Jonathan D. Stevens Alan Y.L. Wong J. Bryan Iorgulescu Anna Y. Tarren Vipheaviny A. Chea Isabel P. Carulli Camilla K. Lemvigh Christina B. Pedersen Ashley K. Gartin Siranush Sarkizova Kyle T. Wright Letitia W. Li Jason Nomburg Shuqiang Li Teddy Huang Xiaoxi Liu Lucas Pomerance Laura M. Doherty Annie M. Apffel Luke J. Wallace Suzanna Rachimi Kristen D. Felt Jacquelyn O. Wolff Elizabeth Witten Wandi Zhang Donna Neuberg William J. Lane Guanglan Zhang Lars R. Olsen Manisha Thakuria Scott J. Rodig Karl R. Clauser Gabriel J. Starrett John G. Doench Sara J. Buhrlage Steven A. Carr James A. DeCaprio Catherine J. Wu Derin B. Keskin |
| author_facet | Patrick C. Lee Susan Klaeger Phuong M. Le Keegan Korthauer Jingwei Cheng Varsha Ananthapadmanabhan Thomas C. Frost Jonathan D. Stevens Alan Y.L. Wong J. Bryan Iorgulescu Anna Y. Tarren Vipheaviny A. Chea Isabel P. Carulli Camilla K. Lemvigh Christina B. Pedersen Ashley K. Gartin Siranush Sarkizova Kyle T. Wright Letitia W. Li Jason Nomburg Shuqiang Li Teddy Huang Xiaoxi Liu Lucas Pomerance Laura M. Doherty Annie M. Apffel Luke J. Wallace Suzanna Rachimi Kristen D. Felt Jacquelyn O. Wolff Elizabeth Witten Wandi Zhang Donna Neuberg William J. Lane Guanglan Zhang Lars R. Olsen Manisha Thakuria Scott J. Rodig Karl R. Clauser Gabriel J. Starrett John G. Doench Sara J. Buhrlage Steven A. Carr James A. DeCaprio Catherine J. Wu Derin B. Keskin |
| author_sort | Patrick C. Lee |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T14:50:46Z |
| format | Article |
| id | doaj.art-60397b52dbf342a38a8b4cfb3371eac6 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-04-13T14:50:46Z |
| publishDate | 2022-07-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-60397b52dbf342a38a8b4cfb3371eac62022-12-22T02:42:37ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-07-0113213Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinomaPatrick C. LeeSusan KlaegerPhuong M. LeKeegan KorthauerJingwei ChengVarsha AnanthapadmanabhanThomas C. FrostJonathan D. StevensAlan Y.L. WongJ. Bryan IorgulescuAnna Y. TarrenVipheaviny A. CheaIsabel P. CarulliCamilla K. LemvighChristina B. PedersenAshley K. GartinSiranush SarkizovaKyle T. WrightLetitia W. LiJason NomburgShuqiang LiTeddy HuangXiaoxi LiuLucas PomeranceLaura M. DohertyAnnie M. ApffelLuke J. WallaceSuzanna RachimiKristen D. FeltJacquelyn O. WolffElizabeth WittenWandi ZhangDonna NeubergWilliam J. LaneGuanglan ZhangLars R. OlsenManisha ThakuriaScott J. RodigKarl R. ClauserGabriel J. StarrettJohn G. DoenchSara J. BuhrlageSteven A. CarrJames A. DeCaprioCatherine J. WuDerin B. KeskinCancers 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.https://doi.org/10.1172/JCI151666Oncology |
| spellingShingle | Patrick C. Lee Susan Klaeger Phuong M. Le Keegan Korthauer Jingwei Cheng Varsha Ananthapadmanabhan Thomas C. Frost Jonathan D. Stevens Alan Y.L. Wong J. Bryan Iorgulescu Anna Y. Tarren Vipheaviny A. Chea Isabel P. Carulli Camilla K. Lemvigh Christina B. Pedersen Ashley K. Gartin Siranush Sarkizova Kyle T. Wright Letitia W. Li Jason Nomburg Shuqiang Li Teddy Huang Xiaoxi Liu Lucas Pomerance Laura M. Doherty Annie M. Apffel Luke J. Wallace Suzanna Rachimi Kristen D. Felt Jacquelyn O. Wolff Elizabeth Witten Wandi Zhang Donna Neuberg William J. Lane Guanglan Zhang Lars R. Olsen Manisha Thakuria Scott J. Rodig Karl R. Clauser Gabriel J. Starrett John G. Doench Sara J. Buhrlage Steven A. Carr James A. DeCaprio Catherine J. Wu Derin B. Keskin Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma The Journal of Clinical Investigation Oncology |
| title | Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma |
| title_full | Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma |
| title_fullStr | Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma |
| title_full_unstemmed | Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma |
| title_short | Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma |
| title_sort | reversal of viral and epigenetic hla class i repression in merkel cell carcinoma |
| topic | Oncology |
| url | https://doi.org/10.1172/JCI151666 |
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