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SHR Neuro Cancer Cardio Lipid Metab Microb
Lyngaa, R; Pedersen, NW; Schrama, D; Thrue, CA; Ibrani, D; Met, O; Thor Straten, P; Nghiem, P; Becker, JC; Hadrup, SR.
T-cell responses to oncogenic merkel cell polyomavirus proteins distinguish patients with merkel cell carcinoma from healthy donors.
Clin Cancer Res. 2014; 20(7):1768-1778
Doi: 10.1158/1078-0432.CCR-13-2697
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- Co-authors Med Uni Graz
- Becker Jürgen Christian
- Schrama David
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- Abstract:
- Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with strong evidence of viral carcinogenesis. The association of MCC with the Merkel cell polyomavirus (MCPyV) may explain the explicit immunogenicity of MCC. Indeed, MCPyV-encoded proteins are likely targets for cytotoxic immune responses to MCC as they are both foreign to the host and necessary to maintain the oncogenic phenotype. However, to date only a single MCPyV-derived CD8 T-cell epitope has been described, thus impeding specific monitoring of T-cell responses to MCC. To overcome this limitation, we scanned the MCPyV oncoprotein large T and small T antigens and the virus capsid protein VP1 for potential T-cell epitopes, and tested for MHC class I affinity. We confirmed the relevance of these epitopes using a high-throughput platform for T-cell enrichment and combinatorial encoding of MHC class I multimers. In peripheral blood from 38 patients with MCC and 30 healthy donors, we identified 53 MCPyV-directed CD8 T-cell responses against 35 different peptide sequences. Strikingly, T-cell responses against oncoproteins were exclusively present in patients with MCC, but not in healthy donors. We further demonstrate both the processing and presentation of the oncoprotein-derived epitopes, as well as the lytic activity of oncoprotein-specific T cells toward MHC-matched MCC cells. Demonstrating the presence of oncoprotein-specific T cells among tumor-infiltrating lymphocytes further substantiated the relevance of the identified epitopes. These T-cell epitopes represent ideal targets for antigen-specific immune therapy of MCC, and enable tracking and characterization of MCPyV-specific immune responses. ©2014 AACR.
- Find related publications in this database (using NLM MeSH Indexing)
- Carcinogenesis - immunology
- Carcinoma, Merkel Cell - diagnosis
- Carcinoma, Merkel Cell - genetics
- Carcinoma, Merkel Cell - virology
- Epitopes - immunology
- Epitopes - isolation & purification
- Humans -
- Immunity, Innate -
- Merkel cell polyomavirus - genetics
- Merkel cell polyomavirus - pathogenicity
- Skin Neoplasms - diagnosis
- Skin Neoplasms - genetics
- Skin Neoplasms - pathology
- Skin Neoplasms - virology
- T-Lymphocytes - immunology
- Viral Proteins - isolation & purification