Title: Merkel polyomavirus-specific T cells fluctuate with merkel cell carcinoma burden and express therapeutically targetable PD-1 and Tim-3 exhaustion markers.
Authors: Afanasiev, Olga K; Yelistratova, Lola; Miller, Natalie; Nagase, Kotaro; Paulson, Kelly; Iyer, Jayasri G; Ibrani, Dafina; Koelle, David M; Nghiem, Paul
Published In Clin Cancer Res, (2013 Oct 01)
Abstract: The persistent expression of Merkel cell polyomavirus (MCPyV) oncoproteins in Merkel cell carcinoma (MCC) provides a unique opportunity to characterize immune evasion mechanisms in human cancer. We isolated MCPyV-specific T cells and determined their frequency and functional status.Multiparameter flow cytometry panels and HLA/peptide tetramers were used to identify and characterize T cells from tumors (n = 7) and blood (n = 18) of patients with MCC and control subjects (n = 10). PD-1 ligand (PD-L1) and CD8 expression within tumors were determined using mRNA profiling (n = 35) and immunohistochemistry (n = 13).MCPyV-specific CD8 T cells were detected directly ex vivo from the blood samples of 7 out of 11 (64%) patients with MCPyV-positive tumors. In contrast, 0 of 10 control subjects had detectable levels of these cells in their blood (P < 0.01). MCPyV-specific T cells in serial blood specimens increased with MCC disease progression and decreased with effective therapy. MCPyV-specific CD8 T cells and MCC-infiltrating lymphocytes expressed higher levels of therapeutically targetable PD-1 and Tim-3 inhibitory receptors compared with T cells specific to other human viruses (P < 0.01). PD-L1 was present in 9 of 13 (69%) MCCs and its expression was correlated with CD8-lymphocyte infiltration.MCC-targeting T cells expand with tumor burden and express high levels of immune checkpoint receptors PD-1 and Tim-3. Reversal of these inhibitory pathways is therefore a promising therapeutic approach for this virus-driven cancer.
PubMed ID: 23922299
MeSH Terms: Antibodies, Viral/immunology; Antigens, Viral/immunology; Antigens, Viral/metabolism; Biomarkers/metabolism; CD8-Positive T-Lymphocytes/immunology; CD8-Positive T-Lymphocytes/metabolism; Carcinoma, Merkel Cell/immunology*; Carcinoma, Merkel Cell/metabolism*; Carcinoma, Merkel Cell/pathology; Carcinoma, Merkel Cell/virology; Case-Control Studies; Hepatitis A Virus Cellular Receptor 2; Immunohistochemistry; Immunophenotyping; Lymphocytes, Tumor-Infiltrating/immunology; Lymphocytes, Tumor-Infiltrating/metabolism; Membrane Proteins/metabolism*; Merkel cell polyomavirus/immunology*; Oncogene Proteins, Viral/immunology; Oncogene Proteins, Viral/metabolism; Programmed Cell Death 1 Receptor/metabolism*; T-Lymphocyte Subsets/immunology*; T-Lymphocyte Subsets/metabolism; Tumor Burden/immunology