Title: Human CD4+ T Cells Specific for Merkel Cell Polyomavirus Localize to Merkel Cell Carcinomas and Target a Required Oncogenic Domain.
Authors: Longino, Natalie V; Yang, Junbao; Iyer, Jayasri G; Ibrani, Dafina; Chow, I-Ting; Laing, Kerry J; Campbell, Victoria L; Paulson, Kelly G; Kulikauskas, Rima M; Church, Candice D; James, Eddie A; Nghiem, Paul; Kwok, William W; Koelle, David M
Published In Cancer Immunol Res, (2019 10)
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.
PubMed ID: 31405946
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