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Merkel cell polyomavirus-specific CD8⁺ and CD4⁺ T-cell responses identified in Merkel cell carcinomas and blood.
Title | Merkel cell polyomavirus-specific CD8⁺ and CD4⁺ T-cell responses identified in Merkel cell carcinomas and blood. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Iyer, JG, Afanasiev, OK, McClurkan, C, Paulson, K, Nagase, K, Jing, L, Marshak, JO, Dong, L, Carter, J, Lai, I, Farrar, E, Byrd, D, Galloway, D, Yee, C, Koelle, DM, Nghiem, P |
Journal | Clin Cancer Res |
Volume | 17 |
Issue | 21 |
Pagination | 6671-80 |
Date Published | 2011 Nov 1 |
ISSN | 1078-0432 |
Keywords | Animals, Antigens, Viral, Tumor, Carcinoma, Merkel Cell, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cercopithecus aethiops, COS Cells, Epitope Mapping, Epitopes, T-Lymphocyte, HLA-A24 Antigen, Humans, Interferon-gamma, Lymphocytes, Tumor-Infiltrating, Merkel cell polyomavirus, Peptides, Polyomavirus Infections, Skin Neoplasms, Tumor Virus Infections |
Abstract | PURPOSE: Merkel cell polyomavirus (MCPyV) is prevalent in the general population, integrates into most Merkel cell carcinomas (MCC), and encodes oncoproteins required for MCC tumor growth. We sought to characterize T-cell responses directed against viral proteins that drive this cancer as a step toward immunotherapy. EXPERIMENTAL DESIGN: Intracellular cytokine cytometry, IFN-γ enzyme-linked immunospot (ELISPOT) assay, and a novel HLA-A*2402-restricted MCPyV tetramer were used to identify and characterize T-cell responses against MCPyV oncoproteins in tumors and blood of MCC patients and control subjects. RESULTS: We isolated virus-reactive CD8 or CD4 T cells from MCPyV-positive MCC tumors (2 of 6) but not from virus-negative tumors (0 of 4). MCPyV-specific T-cell responses were also detected in the blood of MCC patients (14 of 27) and control subjects (5 of 13). These T cells recognized a broad range of peptides derived from capsid proteins (2 epitopes) and oncoproteins (24 epitopes). HLA-A*2402-restricted MCPyV oncoprotein processing and presentation by mammalian cells led to CD8-mediated cytotoxicity. Virus-specific CD8 T cells were markedly enriched among tumor infiltrating lymphocytes as compared with blood, implying intact T-cell trafficking into the tumor. Although tetramer-positive CD8 T cells were detected in the blood of 2 of 5 HLA-matched MCC patients, these cells failed to produce IFN-γ when challenged ex vivo with peptide. CONCLUSIONS: Our findings suggest that MCC tumors often develop despite the presence of T cells specific for MCPyV T-Ag oncoproteins. The identified epitopes may be candidates for peptide-specific vaccines and tumor- or virus-specific adoptive immunotherapies to overcome immune evasion mechanisms in MCC patients. |
DOI | 10.1158/1078-0432.CCR-11-1513 |
Alternate Journal | Clin. Cancer Res. |
PubMed ID | 21908576 |