Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma
Patrick C. Lee, … , Catherine J. Wu, Derin B. Keskin
Patrick C. Lee, … , Catherine J. Wu, Derin B. Keskin
Published July 1, 2022
Citation Information: J Clin Invest. 2022;132(13):e151666. https://doi.org/10.1172/JCI151666.
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Research Article Oncology

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.

Authors

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

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Figure 3

IFN-γ increases and alters the HLA peptidome in MCC.

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IFN-γ increases and alters the HLA peptidome in MCC. (A) Number of detec...
(A) Number of detected peptides presented on HLA-I in MCC lines at baseline (gray bars) and after IFN-γ treatment (red bars). CL, cell line. (B) Correlation heatmap of peptide sequences between MCC lines at baseline and after IFN-γ treatment in motif space. (C) 9-mer motif changes between untreated and IFN-γ–treated samples for MCC-290 (MCPyV–) and MCC-301 (MCPyV+) cell lines. (D) HLA allele distribution of presented peptides detected in cell lines at baseline and after IFN-γ treatment. Each HLA allele is represented by a different color. (E) Summary of changes in peptides presented per HLA gene upon IFN-γ treatment across all MCC lines analyzed for HLA-A (left), -B (middle), and -C (right). (F) Mass spectrum of a detected HLA-A–presented peptide derived from the MCPyV large T antigen (LT) in MCC-367. Red, blue, and green peaks represent y-, b-, and internal ions, respectively, confirming the peptide sequence. Internal ions are labeled with their respective amino acid sequences. MUR, Merkel cell virus T antigen unique region. OBD, origin-binding domain. (G) IFN-γ secretion by PBMCs from patient MCC-367 cocultured in an ELISPOT with DMSO, HIV-GAG negative control peptide, autologous MCC-367 tumor cells, or the LT-derived peptide identified in the MCC-367 HLA peptidome in F. Left: ELISPOT conditions. Right: Summary statistics (n = 3). P values were determined by 1-way ANOVA followed by post hoc Tukey’s multiple-comparison test.