The Journal of Clinical Investigation (Jul 2022)
Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma
- 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
Affiliations
- 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
- Journal volume & issue
-
Vol. 132,
no. 13
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.
