Tumor-Infiltrating Merkel Cell Polyomavirus-Specific T Cells Are Diverse and Associated with Improved Patient Survival

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 re...

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Published in:Cancer immunology research 2017-02, Vol.5 (2), p.137-147
Main Authors: Miller, Natalie J, Church, Candice D, Dong, Lichun, Crispin, David, Fitzgibbon, Matthew P, Lachance, Kristina, Jing, Lichen, Shinohara, Michi, Gavvovidis, Ioannis, Willimsky, Gerald, McIntosh, Martin, Blankenstein, Thomas, Koelle, David M, Nghiem, Paul
Format: Article
Language:English
Subjects:
Carcinoma, Merkel Cell - etiology
Carcinoma, Merkel Cell - mortality
Carcinoma, Merkel Cell - pathology
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - metabolism
Clonal Evolution - genetics
Clonal Evolution - immunology
Epitopes, T-Lymphocyte - chemistry
Epitopes, T-Lymphocyte - genetics
Epitopes, T-Lymphocyte - immunology
Genetic Variation
Humans
Lymphocytes, Tumor-Infiltrating - immunology
Lymphocytes, Tumor-Infiltrating - metabolism
Lymphocytes, Tumor-Infiltrating - pathology
Merkel cell polyomavirus - immunology
Prognosis
Receptors, Antigen, T-Cell, alpha-beta - chemistry
Receptors, Antigen, T-Cell, alpha-beta - genetics
Sequence Analysis, DNA
Skin Neoplasms - etiology
Skin Neoplasms - mortality
Skin Neoplasms - pathology
T-Cell Antigen Receptor Specificity - immunology
T-Lymphocyte Subsets - immunology
T-Lymphocyte Subsets - metabolism
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Summary: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. TCRβ (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 IFNγ 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. Cancer Immunol Res; 5(2); 137-47. ©2017 AACR.
ISSN:2326-6066
2326-6074
DOI:10.1158/2326-6066.CIR-16-0210