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

doi:10.1172/JCI151666

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 NomburgShuqiang 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

^*Corresponding author for this work

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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.

Original language	English
Article number	e151666
Journal	Journal of Clinical Investigation
Volume	132
Issue number	13
Number of pages	16
ISSN	0021-9738
DOIs	https://doi.org/10.1172/JCI151666
Publication status	Published - 2022

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Lee, P. C., Klaeger, S., Le, P. M., Korthauer, K., Cheng, J., Ananthapadmanabhan, V., Frost, T. C., Stevens, J. D., Wong, A. Y. L., Iorgulescu, J. B., Tarren, A. Y., Chea, V. A., Carulli, I. P., Lemvigh, C. K., Pedersen, C. B., Gartin, A. K., Sarkizova, S., Wright, K. T., Li, L. W., ... Keskin, D. B. (2022). Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma. Journal of Clinical Investigation, 132(13), [e151666]. https://doi.org/10.1172/JCI151666

@article{4d0446002eb143bba3aa0d9b02fdd997,

title = "Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma",

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 = "Lee, {Patrick C.} and Susan Klaeger and Le, {Phuong M.} and Keegan Korthauer and Jingwei Cheng and Varsha Ananthapadmanabhan and Frost, {Thomas C.} and Stevens, {Jonathan D.} and Wong, {Alan Y.L.} and Iorgulescu, {J. Bryan} and Tarren, {Anna Y.} and Chea, {Vipheaviny A.} and Carulli, {Isabel P.} and Lemvigh, {Camilla K.} and Pedersen, {Christina B.} and Gartin, {Ashley K.} and Siranush Sarkizova and Wright, {Kyle T.} and Li, {Letitia W.} and Jason Nomburg and Shuqiang Li and Teddy Huang and Xiaoxi Liu and Lucas Pomerance and Doherty, {Laura M.} and Apffel, {Annie M.} and Wallace, {Luke J.} and Suzanna Rachimi and Felt, {Kristen D.} and Wolff, {Jacquelyn O.} and Elizabeth Witten and Wandi Zhang and Donna Neuberg and Lane, {William J.} and Guanglan Zhang and Olsen, {Lars R.} and Manisha Thakuria and Rodig, {Scott J.} and Clauser, {Karl R.} and Starrett, {Gabriel J.} and Doench, {John G.} and Buhrlage, {Sara J.} and Carr, {Steven A.} and DeCaprio, {James A.} and Wu, {Catherine J.} and Keskin, {Derin B.}",

note = "Publisher Copyright: Copyright: {\textcopyright} 2022, Lee et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",

year = "2022",

doi = "10.1172/JCI151666",

language = "English",

volume = "132",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "13",

}

Lee, PC, Klaeger, S, Le, PM, Korthauer, K, Cheng, J, Ananthapadmanabhan, V, Frost, TC, Stevens, JD, Wong, AYL, Iorgulescu, JB, Tarren, AY, Chea, VA, Carulli, IP, Lemvigh, CK, Pedersen, CB, Gartin, AK, Sarkizova, S, Wright, KT, Li, LW, Nomburg, J, Li, S, Huang, T, Liu, X, Pomerance, L, Doherty, LM, Apffel, AM, Wallace, LJ, Rachimi, S, Felt, KD, Wolff, JO, Witten, E, Zhang, W, Neuberg, D, Lane, WJ, Zhang, G, Olsen, LR, Thakuria, M, Rodig, SJ, Clauser, KR, Starrett, GJ, Doench, JG, Buhrlage, SJ, Carr, SA, DeCaprio, JA, Wu, CJ & Keskin, DB 2022, 'Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma', Journal of Clinical Investigation, vol. 132, no. 13, e151666. https://doi.org/10.1172/JCI151666

TY - JOUR

T1 - Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma

AU - Lee, Patrick C.

AU - Klaeger, Susan

AU - Le, Phuong M.

AU - Korthauer, Keegan

AU - Cheng, Jingwei

AU - Ananthapadmanabhan, Varsha

AU - Frost, Thomas C.

AU - Stevens, Jonathan D.

AU - Wong, Alan Y.L.

AU - Iorgulescu, J. Bryan

AU - Tarren, Anna Y.

AU - Chea, Vipheaviny A.

AU - Carulli, Isabel P.

AU - Lemvigh, Camilla K.

AU - Pedersen, Christina B.

AU - Gartin, Ashley K.

AU - Sarkizova, Siranush

AU - Wright, Kyle T.

AU - Li, Letitia W.

AU - Nomburg, Jason

AU - Li, Shuqiang

AU - Huang, Teddy

AU - Liu, Xiaoxi

AU - Pomerance, Lucas

AU - Doherty, Laura M.

AU - Apffel, Annie M.

AU - Wallace, Luke J.

AU - Rachimi, Suzanna

AU - Felt, Kristen D.

AU - Wolff, Jacquelyn O.

AU - Witten, Elizabeth

AU - Zhang, Wandi

AU - Neuberg, Donna

AU - Lane, William J.

AU - Zhang, Guanglan

AU - Olsen, Lars R.

AU - Thakuria, Manisha

AU - Rodig, Scott J.

AU - Clauser, Karl R.

AU - Starrett, Gabriel J.

AU - Doench, John G.

AU - Buhrlage, Sara J.

AU - Carr, Steven A.

AU - DeCaprio, James A.

AU - Wu, Catherine J.

AU - Keskin, Derin B.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

U2 - 10.1172/JCI151666

DO - 10.1172/JCI151666

M3 - Journal article

C2 - 35775490

AN - SCOPUS:85133304845

SN - 0021-9738

VL - 132

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 13

M1 - e151666

ER -

Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma

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