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Cancer Immunol Res. 2019 Oct;7(10):1727-1739. doi: 10.1158/2326-6066.CIR-19-0103. Epub 2019 Aug 12.

Human CD4+ T Cells Specific for Merkel Cell Polyomavirus Localize to Merkel Cell Carcinomas and Target a Required Oncogenic Domain.

Author information

1
Department of Medicine, Division of Dermatology, University of Washington, Seattle, Washington.
2
Department of Pathology, University of Washington, Seattle, Washington.
3
Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington.
4
Department of Medicine, Division of Allergy and Infectious Disease, University of Washington, Seattle, Washington.
5
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
6
Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, Washington.
7
Department of Medicine, Division of Dermatology, University of Washington, Seattle, Washington. pnghiem@uw.edu.
8
Department of Laboratory Medicine, University of Washington, Seattle, Washington.
9
Department of Global Health, University of Washington, Seattle, Washington.
10
Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
#
Contributed equally

Abstract

Although CD4+ T cells likely play key roles in antitumor immune responses, most immuno-oncology studies have been limited to CD8+ T-cell responses due to multiple technical barriers and a lack of shared antigens across patients. Merkel cell carcinoma (MCC) is an aggressive skin cancer caused by Merkel cell polyomavirus (MCPyV) oncoproteins in 80% of cases. Because MCPyV oncoproteins are shared across most patients with MCC, it is unusually feasible to identify, characterize, and potentially augment tumor-specific CD4+ T cells. Here, we report the identification of CD4+ T-cell responses against six MCPyV epitopes, one of which included a conserved, essential viral oncogenic domain that binds/disables the cellular retinoblastoma (Rb) tumor suppressor. We found that this epitope (WEDLT209-228) could be presented by three population-prevalent HLA class II alleles, making it a relevant target in 64% of virus-positive MCC patients. Cellular staining with a WEDLT209-228-HLA-DRB1*0401 tetramer indicated that specific CD4+ T cells were detectable in 78% (14 of 18) of evaluable MCC patients, were 250-fold enriched within MCC tumors relative to peripheral blood, and had diverse T-cell receptor sequences. We also identified a modification of this domain that still allowed recognition by these CD4+ T cells but disabled binding to the Rb tumor suppressor, a key step in the detoxification of a possible therapeutic vaccine. The use of these new tools for deeper study of MCPyV-specific CD4+ T cells may provide broader insight into cancer-specific CD4+ T-cell responses.

PMID:
31405946
PMCID:
PMC6774871
[Available on 2020-04-01]
DOI:
10.1158/2326-6066.CIR-19-0103

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