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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • CD4-Positive T-Lymphocytes / immunology*
  • Carcinogenesis / immunology*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Carcinoma, Merkel Cell / drug therapy
  • Carcinoma, Merkel Cell / immunology*
  • Carcinoma, Merkel Cell / metabolism
  • Carcinoma, Merkel Cell / pathology
  • Cell Line, Tumor
  • Epitopes / immunology*
  • Healthy Volunteers
  • Humans
  • Merkel cell polyomavirus / immunology*
  • Oligopeptides / immunology
  • Retinoblastoma Protein / metabolism
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology

Substances

  • Epitopes
  • Oligopeptides
  • Retinoblastoma Protein