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

• Published in: Clinical cancer research Vol. 17; no. 21; pp. 6671 - 6680
• Main Authors: Iyer, Jayasri G., Afanasiev, Olga K., McClurkan, Christopher, Paulson, Kelly, Nagase, Kotaro, Jing, Lichen, Marshak, Joshua O., Dong, Lichun, Carter, Joseph, Lai, Ivy, Farrar, Erik, Byrd, David, Galloway, Denise, Yee, Cassian, Koelle, David M., Nghiem, Paul
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.11.2011
• Subjects: Animals; Antigens, Viral, Tumor - immunology; Antineoplastic agents; Biological and medical sciences; Carcinoma, Merkel Cell - blood; Carcinoma, Merkel Cell - immunology; Carcinoma, Merkel Cell - virology; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Chlorocebus aethiops; COS Cells; Dermatology; Epitope Mapping; Epitopes, T-Lymphocyte - immunology; HLA-A24 Antigen - immunology; Humans; Interferon-gamma - biosynthesis; Interferon-gamma - immunology; Lymphocytes, Tumor-Infiltrating - immunology; Medical sciences; Merkel cell polyomavirus - immunology; Peptides - immunology; Pharmacology. Drug treatments; Polyomavirus; Polyomavirus Infections - blood; Polyomavirus Infections - immunology; Polyomavirus Infections - virology; Skin Neoplasms - blood; Skin Neoplasms - immunology; Skin Neoplasms - virology; Tumor Virus Infections - blood; Tumor Virus Infections - immunology; Tumor Virus Infections - virology; Tumors of the skin and soft tissue. Premalignant lesions; Biological fluid; Skin disease; CD4 T lymphocyte; Immune response; Merkel cell carcinoma; T-Lymphocyte; Malignant tumor; Blood; Cancer
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-1513

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.