• Clin Cancer Res · Oct 2013

    Merkel polyomavirus-specific T cells fluctuate with merkel cell carcinoma burden and express therapeutically targetable PD-1 and Tim-3 exhaustion markers.

    • Olga K Afanasiev, Lola Yelistratova, Natalie Miller, Kotaro Nagase, Kelly Paulson, Jayasri G Iyer, Dafina Ibrani, David M Koelle, and Paul Nghiem.
    • Authors' Affiliations: Departments of Medicine/Dermatology, Pathology, Medicine, Laboratory Medicine, Global Health, University of Washington; Fred Hutchinson Cancer Research Center; Benaroya Research Institute, Seattle, Washington; and Department of Medicine/Dermatology, Saga University, Nabeshima, Japan.
    • Clin Cancer Res. 2013 Oct 1; 19 (19): 5351-60.

    PurposeThe 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 DesignMultiparameter 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).ResultsMCPyV-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.ConclusionsMCC-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.©2013 AACR.

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