Merkel Polyomavirus-Specific T Cells Fluctuate with Merkel Cell Carcinoma Burden and Express Therapeutically Targetable PD-1 and Tim-3 Exhaustion Markers

• Published in: Clinical cancer research Vol. 19; no. 19; pp. 5351 - 5360
• Main Authors: Afanasiev, Olga K., Yelistratova, Lola, Miller, Natalie, Nagase, Kotaro, Paulson, Kelly, Iyer, Jayasri G., Ibrani, Dafina, Koelle, David M., Nghiem, Paul
• Format: Journal Article
• Language: English
• Published: United States 01.10.2013
• Subjects: Antibodies, Viral - immunology; Antigens, Viral - immunology; Antigens, Viral - metabolism; Biomarkers - metabolism; Carcinoma, Merkel Cell - immunology; Carcinoma, Merkel Cell - metabolism; Carcinoma, Merkel Cell - pathology; Carcinoma, Merkel Cell - virology; Case-Control Studies; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; 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; Polyomavirus; Programmed Cell Death 1 Receptor - metabolism; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Tumor Burden - immunology
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-13-0035

Purpose: 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. Experimental Design: 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). Results: 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. Conclusions: 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. Clin Cancer Res; 19(19); 5351–60. ©2013 AACR.