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Tumor-infiltrating merkel cell polyomavirus-specific T cells are diverse and associated with improved patient survival

Item Type:Article
Title:Tumor-infiltrating merkel cell polyomavirus-specific T cells are diverse and associated with improved patient survival
Creators Name:Miller, N.J. and Church, C.D. and Dong, L. and Crispin, D. and Fitzgibbon, M.P. and Lachance, K. and Jing, L. and Shinohara, M. and Gavvovidis, I. and Willimsky, G. and McIntosh, M. and Blankenstein, T. and Koelle, D.M. and Nghiem, P.
Abstract:Tumor-infiltrating CD8(+) T cells are associated with improved survival of patients with Merkel cell carcinoma (MCC), an aggressive skin cancer causally linked to Merkel cell polyomavirus (MCPyV). However, CD8(+) T-cell infiltration is robust in only 4% to 18% of MCC tumors. We characterized the T-cell receptor (TCR) repertoire restricted to one prominent epitope of MCPyV (KLLEIAPNC, "KLL") and assessed whether TCR diversity, tumor infiltration, or T-cell avidity correlated with clinical outcome. HLA-A*02:01/KLL tetramer(+) CD8(+) T cells from MCC patient peripheral blood mononuclear cells (PBMC) and tumor-infiltrating lymphocytes (TIL) were isolated via flow cytometry. TCR{beta} (TRB) sequencing was performed on tetramer(+) cells from PBMCs or TILs (n = 14) and matched tumors (n = 12). Functional avidity of T-cell clones was determined by IFN{gamma} production. We identified KLL tetramer(+) T cells in 14% of PBMC and 21% of TIL from MCC patients. TRB repertoires were strikingly diverse (397 unique TRBs were identified from 12 patients) and mostly private (only one TCRb clonotype shared between two patients). An increased fraction of KLL-specific TIL (>1.9%) was associated with significantly increased MCC-specific survival P = 0.0009). T-cell cloning from four patients identified 42 distinct KLL-specific TCRa/b pairs. T-cell clones from patients with improved MCC-specific outcomes were more avid (P < 0.05) and recognized an HLA-appropriate MCC cell line. T cells specific for a single MCPyV epitope display marked TCR diversity within and between patients. Intratumoral infiltration by MCPyV-specific T cells was associated with significantly improved MCC-specific survival, suggesting that augmenting the number or avidity of virus-specific T cells may have therapeutic benefit.
Keywords:CD8-Positive T-Lymphocytes, Carcinoma, Merkel Cell, Clonal Evolution, Epitopes, T-Lymphocyte, Genetic Variation, Lymphocytes, Tumor-Infiltrating, Merkel Cell Polyomavirus, Prognosis, Receptors, Antigen, T-Cell, Alpha-Beta, Sequence Analysis, DNA, Skin Neoplasms, T-Cell Antigen Receptor Specificity, T-Lymphocyte Subsets
Source:Cancer Immunology Research
Publisher:American Association for Cancer Research
Page Range:137-147
Date:February 2017
Official Publication:https://doi.org/10.1158/2326-6066.CIR-16-0210
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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