Merkel Cell Polyomavirus-Specific CD8+ and CD4+ T-cell Responses Identified in Merkel Cell Carcinomas and Blood.

Publication Type:

Journal Article

Source:

Clinical cancer research : an official journal of the American Association for Cancer Research, Volume 317, Issue 21, p.6671-6680 (2011)

Keywords:

2011, Animals, Antigens, Viral, Tumor, Carcinoma, Merkel Cell, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Center-Authored Paper, Cercopithecus aethiops, Clinical Research Division, COS Cells, Epitope Mapping, Epitopes, T-Lymphocyte, Flow Cytometry Core Facility, HLA-A24 Antigen, Human Biology Division, Humans, Immune Monitoring Core Facility, interferon-gamma, Lymphocytes, Tumor-Infiltrating, Merkel cell polyomavirus, October 2011, Peptides, Polyomavirus Infections, Public Health Sciences Division, Scientific Imaging Core Facility, Shared Resources, Skin Neoplasms, Tumor Virus Infections, Vaccine and Infectious Disease Division

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. Clin Cancer Res; 17(21); 1-10. ©2011 AACR.