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Cancer Immunology Research
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Research Articles

Prevalent and Diverse Intratumoral Oncoprotein-Specific CD8+ T Cells within Polyomavirus-Driven Merkel Cell Carcinomas

Lichen Jing, Mariliis Ott, Candice D. Church, Rima M. Kulikauskas, Dafina Ibrani, Jayasri G. Iyer, Olga K. Afanasiev, Aric Colunga, Maclean M. Cook, Hong Xie, Alexander L. Greninger, Kelly G. Paulson, Aude G. Chapuis, Shailender Bhatia, Paul Nghiem and David M. Koelle
Lichen Jing
1Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington.
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Mariliis Ott
1Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington.
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Candice D. Church
2Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington.
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  • ORCID record for Candice D. Church
Rima M. Kulikauskas
2Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington.
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Dafina Ibrani
2Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington.
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Jayasri G. Iyer
2Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington.
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Olga K. Afanasiev
2Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington.
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Aric Colunga
2Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington.
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Maclean M. Cook
2Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington.
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Hong Xie
3Department of Laboratory Medicine, University of Washington, Seattle, Washington.
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Alexander L. Greninger
3Department of Laboratory Medicine, University of Washington, Seattle, Washington.
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Kelly G. Paulson
4Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington.
5Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
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Aude G. Chapuis
4Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington.
5Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
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Shailender Bhatia
4Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington.
5Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
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Paul Nghiem
2Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington.
5Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
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David M. Koelle
1Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington.
3Department of Laboratory Medicine, University of Washington, Seattle, Washington.
6Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
7Department of Global Health, University of Washington, Seattle, Washington.
8Benaroya Research Institute, Seattle, Washington.
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  • For correspondence: dkoelle@medicine.washington.edu
DOI: 10.1158/2326-6066.CIR-19-0647 Published May 2020
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Abstract

Merkel cell carcinoma (MCC) is often caused by persistent expression of Merkel cell polyomavirus (MCPyV) T-antigen (T-Ag). These non-self proteins comprise about 400 amino acids (AA). Clinical responses to immune checkpoint inhibitors, seen in about half of patients, may relate to T-Ag–specific T cells. Strategies to increase CD8+ T-cell number, breadth, or function could augment checkpoint inhibition, but vaccines to augment immunity must avoid delivery of oncogenic T-antigen domains. We probed MCC tumor-infiltrating lymphocytes (TIL) with an artificial antigen-presenting cell (aAPC) system and confirmed T-Ag recognition with synthetic peptides, HLA-peptide tetramers, and dendritic cells (DC). TILs from 9 of 12 (75%) subjects contained CD8+ T cells recognizing 1–8 MCPyV epitopes per person. Analysis of 16 MCPyV CD8+ TIL epitopes and prior TIL data indicated that 97% of patients with MCPyV+ MCC had HLA alleles with the genetic potential that restrict CD8+ T-cell responses to MCPyV T-Ag. The LT AA 70–110 region was epitope rich, whereas the oncogenic domains of T-Ag were not commonly recognized. Specific recognition of T-Ag–expressing DCs was documented. Recovery of MCPyV oncoprotein–specific CD8+ TILs from most tumors indicated that antigen indifference was unlikely to be a major cause of checkpoint inhibition failure. The myriad of epitopes restricted by diverse HLA alleles indicates that vaccination can be a rational component of immunotherapy if tumor immune suppression can be overcome, and the oncogenic regions of T-Ag can be modified without impacting immunogenicity.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Prior presentation: Presented in part at the Keystone Conference on Cancer Vaccines, Vancouver, BC, Canada, January 20–24, 2019, as an abstract (abstract number 2001).

  • Cancer Immunol Res 2020;8:648–59

  • Received September 8, 2019.
  • Revision received December 16, 2019.
  • Accepted March 9, 2020.
  • Published first March 16, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 8 (5)
May 2020
Volume 8, Issue 5
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Prevalent and Diverse Intratumoral Oncoprotein-Specific CD8+ T Cells within Polyomavirus-Driven Merkel Cell Carcinomas
Lichen Jing, Mariliis Ott, Candice D. Church, Rima M. Kulikauskas, Dafina Ibrani, Jayasri G. Iyer, Olga K. Afanasiev, Aric Colunga, Maclean M. Cook, Hong Xie, Alexander L. Greninger, Kelly G. Paulson, Aude G. Chapuis, Shailender Bhatia, Paul Nghiem and David M. Koelle
Cancer Immunol Res May 1 2020 (8) (5) 648-659; DOI: 10.1158/2326-6066.CIR-19-0647

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Prevalent and Diverse Intratumoral Oncoprotein-Specific CD8+ T Cells within Polyomavirus-Driven Merkel Cell Carcinomas
Lichen Jing, Mariliis Ott, Candice D. Church, Rima M. Kulikauskas, Dafina Ibrani, Jayasri G. Iyer, Olga K. Afanasiev, Aric Colunga, Maclean M. Cook, Hong Xie, Alexander L. Greninger, Kelly G. Paulson, Aude G. Chapuis, Shailender Bhatia, Paul Nghiem and David M. Koelle
Cancer Immunol Res May 1 2020 (8) (5) 648-659; DOI: 10.1158/2326-6066.CIR-19-0647
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