Merkel cell polyomavirus-specific CD8⁺ and CD4⁺ T-cell responses identified in Merkel cell carcinomas and blood
| Autor: | Paul Nghiem, Joshua O. Marshak, Joseph J. Carter, Erik A. Farrar, Olga K. Afanasiev, Ivy Lai, Lichun Dong, Kotaro Nagase, Christopher M. McClurkan, Kelly G. Paulson, Denise A. Galloway, David R. Byrd, Cassian Yee, Jayasri G. Iyer, Lichen Jing, David M. Koelle |
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| Rok vydání: | 2011 |
| Předmět: |
CD4-Positive T-Lymphocytes
Cancer Research Skin Neoplasms medicine.medical_treatment Merkel cell polyomavirus Epitopes T-Lymphocyte HLA-A24 Antigen Biology CD8-Positive T-Lymphocytes Epitope Article Interferon-gamma Lymphocytes Tumor-Infiltrating Antigen Chlorocebus aethiops medicine Cytotoxic T cell Animals Humans Antigens Viral Tumor Polyomavirus Infections Tumor-infiltrating lymphocytes food and beverages Immunotherapy biology.organism_classification Carcinoma Merkel Cell Tumor Virus Infections medicine.anatomical_structure Oncology Immunology COS Cells Merkel cell Peptides CD8 Epitope Mapping |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 17(21) |
| ISSN: | 1557-3265 |
| Popis: | 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. Clin Cancer Res; 17(21); 6671–80. ©2011 AACR. |
| Databáze: | OpenAIRE |
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